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1
Beal, M. Flint. "Mitochondria, NO and neurodegeneration." Biochemical Society Symposia 66 (September 1, 1999): 43–54. http://dx.doi.org/10.1042/bss0660043.
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A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.
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Rebelo, Adriana P., Ilse Eidhof, Vivian P. Cintra, Léna Guillot-Noel, Claudia V. Pereira, Dagmar Timmann, Andreas Traschütz, et al. "Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia." Brain 144, no. 5 (April 23, 2021): 1467–81. http://dx.doi.org/10.1093/brain/awab071.
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Abstract Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1–PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.
3
Gomes, Cláudio M., and Renata Santos. "Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/487534.
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Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of theFXNgene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with anα/βsandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in theFXNcoding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.
4
Desai, Shyamal, Meredith Juncker, and Catherine Kim. "Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases." Experimental Biology and Medicine 243, no. 6 (January 9, 2018): 554–62. http://dx.doi.org/10.1177/1535370217752351.
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Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.
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Rodríguez, Laura R., Tamara Lapeña-Luzón, Noelia Benetó, Vicent Beltran-Beltran, Federico V. Pallardó, Pilar Gonzalez-Cabo, and Juan Antonio Navarro. "Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?" Antioxidants 11, no. 1 (January 15, 2022): 165. http://dx.doi.org/10.3390/antiox11010165.
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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.
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Qi, Fei, Qingmei Meng, Ikue Hayashi, and Junya Kobayashi. "FXR1 is a novel MRE11-binding partner and participates in oxidative stress responses." Journal of Radiation Research 61, no. 3 (March 25, 2020): 368–75. http://dx.doi.org/10.1093/jrr/rraa011.
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Abstract Ataxia-telangiectasia (AT) and MRE11-defective Ataxia-telangiectasia-like disorder (ATLD) patients show progressive cerebellar ataxia. ATM, mutated in AT, can be activated in response to oxidative stress as well as DNA damage, which could be linked to disease-related neurodegeneration. However, the role of MRE11 in oxidative stress responses has been elusive. Here, we showed that MRE11 could participate in ATM activation during oxidative stress in an NBS1/RAD50-independent manner. Importantly, MRE11 was indispensable for ATM activation. We identified FXR1 as a novel MRE11-binding partner by mass spectrometry. We confirmed that FXR1 could bind with MRE11 and showed that both localize to the cytoplasm. Notably, MRE11 and FXR1 partly localize to the mitochondria, which are the major source of cytoplasmic reactive oxygen species (ROS). The contribution of FXR1 to DNA double-strand break damage responses seemed minor and limited to HR repair, considering that depletion of FXR1 perturbed chromatin association of homologous recombination repair factors and sensitized cells to camptothecin. During oxidative stress, depletion of FXR1 by siRNA reduced oxidative stress responses and increased the sensitivity to pyocyanin, a mitochondrial ROS inducer. Collectively, our findings suggest that MRE11 and FXR1 might contribute to cellular defense against mitochondrial ROS as a cytoplasmic complex.
7
Giulivi, Cecilia, Eleonora Napoli, Flora Tassone, Julian Halmai, and Randi Hagerman. "Plasma metabolic profile delineates roles for neurodegeneration, pro-inflammatory damage and mitochondrial dysfunction in the FMR1 premutation." Biochemical Journal 473, no. 21 (October 27, 2016): 3871–88. http://dx.doi.org/10.1042/bcj20160585.
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Carriers of premutation CGG expansions in the fragile X mental retardation 1 (FMR1) gene are at higher risk of developing a late-onset neurodegenerative disorder named Fragile X-associated tremor ataxia syndrome (FXTAS). Given that mitochondrial dysfunction has been identified in fibroblasts, PBMC and brain samples from carriers as well as in animal models of the premutation and that mitochondria are at the center of intermediary metabolism, the aim of the present study was to provide a complete view of the metabolic pattern by uncovering plasma metabolic perturbations in premutation carriers. To this end, metabolic profiles were evaluated in plasma from 23 premutation individuals and 16 age- and sex-matched controls. Among the affected pathways, mitochondrial dysfunction was associated with a Warburg-like shift with increases in lactate levels and altered Krebs' intermediates, neurotransmitters, markers of neurodegeneration and increases in oxidative stress-mediated damage to biomolecules. The number of CGG repeats correlated with a subset of plasma metabolites, which are implicated not only in mitochondrial disorders but also in other neurological diseases, such as Parkinson's, Alzheimer's and Huntington's diseases. For the first time, the identified pathways shed light on disease mechanisms contributing to morbidity of the premutation, with the potential of assessing metabolites in longitudinal studies as indicators of morbidity or disease progression, especially at the early preclinical stages.
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Brown, Collis, Tamaro Hudson, and Sonya K. Sobrian. "95355 Potential Drug Therapy for Fragile X Tremor/Ataxia Syndrome." Journal of Clinical and Translational Science 5, s1 (March 2021): 91. http://dx.doi.org/10.1017/cts.2021.635.
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ABSTRACT IMPACT: The ability to restore mitochondrial health in neurons derived from FXTAS patient-induced pluripotent stem cells by novel natural compounds is critically important to the management of patients experiencing this syndrome and other Fragile X associated disorders. OBJECTIVES/GOALS: The goal of this research is to assess the biological potency of MAM, NADA and MAM analogues’ neuroprotective capacity with respect to mitochondrial damage, and antioxidant properties that can restore mitochondrial health in patients with FXTAS. METHODS/STUDY POPULATION: To establish mitochondrial dysfunction, normal human cell lines and human induced pluripotent cells will be exposed to multiple concentrations of glucose/ glucose oxidase (GluOx) at several time points to induce varying intensities of oxidative stress. The degrees of oxidative stress will be measured by apoptosis and mitochondrial reactive oxygen species (ROS) production. N-arachidonoyldopamine (NADA), macamides (MAM) and its analogue compounds, effective against oxidative damage in mitochondria, will be used to rescue glucose oxidase induced oxidative damage in both cell lines. To test the ability of these drugs to restore mitochondrial health, cell viability and cellular superoxide production will be assessed by propidium iodide and the MitoSox fluorescence assay, respectively. RESULTS/ANTICIPATED RESULTS: We anticipate that GluOx at varying concentrations and time points will proportionally increase levels of apoptosis and mitochondrial ROS, reflective of mitochondrial damage, with the most severe dysfunction occurring at the maximum dose of 40µM and the longest duration of 72-hr exposure. Moreover, administration of NADA, MAM, and MAM analogues at seven concentrations, ranging from 10-8 to 10-5 M in half-log increments, will successfully treat the oxidative defects induced in the cell lines by decreasing apoptosis, and superoxide production, and increasing cell viability. DISCUSSION/SIGNIFICANCE OF FINDINGS: This research allows for the development of an in vitro neuronal model of FXTAS, lends flexibility to testing therapeutics, and expands the discovery of mitochondrial biomedical markers for the syndrome. Data generated should inform mechanistic studies of the relationship between mitochondrial damage and FXTAS-induce neurodegeneration.
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Wang, Heling, Sofie Lautrup, Domenica Caponio, Jianying Zhang, and Evandro Fang. "DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 13 (June 23, 2021): 6748. http://dx.doi.org/10.3390/ijms22136748.
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DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.
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Wang, Mei-Jen, Hsin-Yi Huang, Tsung-Lang Chiu, Hui-Fen Chang, and Hsin-Rong Wu. "Peroxiredoxin 5 Silencing Sensitizes Dopaminergic Neuronal Cells to Rotenone via DNA Damage-Triggered ATM/p53/PUMA Signaling-Mediated Apoptosis." Cells 9, no. 1 (December 19, 2019): 22. http://dx.doi.org/10.3390/cells9010022.
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Peroxiredoxins (Prxs) are a family of thioredoxin peroxidases. Accumulating evidence suggests that changes in the expression of Prxs may be involved in neurodegenerative diseases pathology. However, the expression and function of Prxs in Parkinson’s disease (PD) remains unclear. Here, we showed that Prx5 was the most downregulated of the six Prx subtypes in dopaminergic (DA) neurons in rotenone-induced cellular and rat models of PD, suggesting possible roles in regulating their survival. Depletion of Prx5 sensitized SH-SY5Y DA neuronal cells to rotenone-induced apoptosis. The extent of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation was increased by Prx5 loss. Furthermore, Prx5 knockdown enhanced the induction of PUMA by rotenone through a p53-dependent mechanism. Using RNA interference approaches, we demonstrated that the p53/PUMA signaling was essential for Prx5 silencing-exacerbated mitochondria-driven apoptosis. Additionally, downregulation of Prx5 augmented rotenone-induced DNA damage manifested as induction of phosphorylated histone H2AX (γ-H2AX) and activation of ataxia telangiectasia mutated (ATM) kinase. The pharmacological inactivation of ATM revealed that ATM was integral to p53 activation by DNA damage. These findings provided a novel link between Prx5 and DNA damage-triggered ATM/p53/PUMA signaling in a rotenone-induced PD model. Thus, Prx5 might play an important role in protection against rotenone-induced DA neurodegeneration.
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Harmuth, Tina, Jonasz J. Weber, Anna J. Zimmer, Anna S. Sowa, Jana Schmidt, Julia C. Fitzgerald, Ludger Schöls, Olaf Riess, and Jeannette Hübener-Schmid. "Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3 Is Linked to VDAC1 Deubiquitination." International Journal of Molecular Sciences 23, no. 11 (May 25, 2022): 5933. http://dx.doi.org/10.3390/ijms23115933.
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Dysfunctional mitochondria are linked to several neurodegenerative diseases. Metabolic defects, a symptom which can result from dysfunctional mitochondria, are also present in spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, the most frequent, dominantly inherited neurodegenerative ataxia worldwide. Mitochondrial dysfunction has been reported for several neurodegenerative disorders and ataxin-3 is known to deubiquitinylate parkin, a key protein required for canonical mitophagy. In this study, we analyzed mitochondrial function and mitophagy in a patient-derived SCA3 cell model. Human fibroblast lines isolated from SCA3 patients were immortalized and characterized. SCA3 patient fibroblasts revealed circular, ring-shaped mitochondria and featured reduced OXPHOS complexes, ATP production and cell viability. We show that wildtype ataxin-3 deubiquitinates VDAC1 (voltage-dependent anion channel 1), a member of the mitochondrial permeability transition pore and a parkin substrate. In SCA3 patients, VDAC1 deubiquitination and parkin recruitment to the depolarized mitochondria is inhibited. Increased p62-linked mitophagy, autophagosome formation and autophagy is observed under disease conditions, which is in line with mitochondrial fission. SCA3 fibroblast lines demonstrated a mitochondrial phenotype and dysregulation of parkin-VDAC1-mediated mitophagy, thereby promoting mitochondrial quality control via alternative pathways.
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Ambrose, Mark, and Richard A. Gatti. "Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions." Blood 121, no. 20 (May 16, 2013): 4036–45. http://dx.doi.org/10.1182/blood-2012-09-456897.
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In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients—children and adults alike—which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.
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Kakhlon, Or, William Breuer, Arnold Munnich, and Z. Ioav Cabantchik. "Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulationThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease." Canadian Journal of Physiology and Pharmacology 88, no. 3 (March 2010): 187–96. http://dx.doi.org/10.1139/y09-128.
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Defective iron utilization leading to either systemic or regional misdistribution of the metal has been identified as a critical feature of several different disorders. Iron concentrations can rise to toxic levels in mitochondria of excitable cells, often leaving the cytosol iron-depleted, in some forms of neurodegeneration with brain accumulation (NBIA) or following mutations in genes associated with mitochondrial functions, such as ABCB7 in X-linked sideroblastic anemia with ataxia (XLSA/A) or the genes encoding frataxin in Friedreich’s ataxia (FRDA). In anemia of chronic disease (ACD), iron is withheld by macrophages, while iron levels in extracellular fluids (e.g., plasma) are drastically reduced. One possible therapeutic approach to these diseases is iron chelation, which is known to effectively reduce multiorgan iron deposition in iron-overloaded patients. However, iron chelation is probably inappropriate for disorders associated with misdistribution of iron within selected tissues or cells. One chelator in clinical use for treating iron overload, deferiprone (DFP), has been identified as a reversed siderophore, that is, an agent with iron-relocating abilities in settings of regional iron accumulation. DFP was applied to a cell model of FRDA, a paradigm of a disorder etiologically associated with cellular iron misdistribution. The treatment reduced the mitochondrial levels of labile iron pools (LIP) that were increased by frataxin deficiency. DFP also conferred upon cells protection against oxidative damage and concomitantly mediated the restoration of various metabolic parameters, including aconitase activity. Administration of DFP to FRDA patients for 6 months resulted in selective and significant reduction in foci of brain iron accumulation (assessed by T2* MRI) and initial functional improvements, with only minor changes in net body iron stores. The prospects of drug-mediated iron relocation versus those of chelation are discussed in relation to other disorders involving iron misdistribution, such as ACD and XLSA/A.
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Merkel, Drorit, H. Joachim Deeg, Amos Simon, Ninette Amariglio, Arnon Nagler, and Gideon Rechavi. "Somatic Expansion of the Frataxin Gene GAA Repeats in MDS Patients." Blood 112, no. 11 (November 16, 2008): 1642. http://dx.doi.org/10.1182/blood.v112.11.1642.1642.
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Abstract The mitochondria play an important role in both apoptosis and heme synthesis. In patients with Myelodysplastic syndrome (MDS) the marrow is characterized by defective hematopoiesis, increased apoptosis and the presence of iron laden mitochondria. The molecular mechanisms responsible for increased apoptosis remain incompletely understood. Frederic’s ataxia (FRDA), the most common inherited ataxia, is a severe autosomal-recessive disease characterized by neurodegeneration, cardiomyopathy and diabetes, resulting from reduced synthesis of the mitochondrial protein frataxin which is involved in mitochondrial energy production and other cellular functions by providing iron for heme synthesis and iron–sulfur cluster (ISC) assembly and repair, serving as a Fe (II) donor for ferrochelatase. The underlying mutation consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene. Long expansions of a GAA tri-nucleotide in FRDA patients range from 66 to more than 1,700 repeats, whereas the normal range of repeats varies from 7 to 36. Abnormal expansion results in reduced frataxin mRNA levels, leading to reduced function of the respiratory chain. The aim of the present study was to determine if frataxin gene mutations occurred in MDS patients. We analyzed DNA from peripheral blood (PB) of 29 MDS patients and from 22 healthy marrow (BM) donors using repeat-Primed PCR. We also sampled genomic DNA products from buccal smears of the MDS patients. In MDS patients PCR of PB in 9 out of 24 patients (37%) showed short length (2–8 repeats), whereas PB of the remaining 15 patients (62.5%) showed longer PCR products (10–43 repeats, still in the “normal” range for FRDA). The PCR products of the buccal smears from all 14 patient samples were short (2–7 repeats), including those from 9 patients who had longer repeats in PB. In healthy BM donors, PCR of PB detected short length repeats (4–5 repeats) in17 of 20 individuals (85%), whereas 3 samples (15%) had longer PCR products (11–26 repeats). This was statistically significantly different from patients with MDS (P= 0.0014). The results indicate that MDS patients exhibit longer frataxin gene products than healthy individuals in PB, but not in buccal DNA. These data suggest a somatic mutation in the frataxin gene in hematopoetic cells of patients with MDS. Further studies will explore the impact of this mutation on mitochondrial function and on the pathophysiology of MDS.
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Fagerberg, Christina R., Adrian Taylor, Felix Distelmaier, Henrik D. Schrøder, Maria Kibæk, Dagmar Wieczorek, Mark Tarnopolsky, et al. "Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration." Brain 143, no. 1 (December 19, 2019): 94–111. http://dx.doi.org/10.1093/brain/awz376.
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Abstract Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.
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Wu, Yu-Ling, Jui-Chih Chang, Yi-Chun Chao, Hardy Chan, Mingli Hsieh, and Chin-San Liu. "In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3." Antioxidants 11, no. 7 (July 18, 2022): 1389. http://dx.doi.org/10.3390/antiox11071389.
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Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD78) to clarify the resulting pathological mechanism by assaying mitochondrial function, mutant ataxin-3 protein toxicity, and oxidative stress. JM17, 1 μM, comprehensively restored mitochondrial function, decreased mutant protein aggregates, and attenuated intracellular/mitochondrial reactive oxygen species (ROS) levels. Although JM17 induced dose-dependent Nrf2 activation, a low dose of JM17 (less than 5 μM) still had a better antioxidant ability compared to the other Nrf2 activators and specifically increased mitochondrial superoxide dismutase 2 in an Nrf2-dependent manner as shown by knockdown experiments with siRNA. It showed that activation of Nrf2 in response to ROS generated in mitochondria could play an import role in the benefit of JM17. This study presents the diversified regulation of JM17 in a pathological process and helped develop more effective therapeutic strategies for SCA3.
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Braga Neto, Pedro, José Luiz Pedroso, Sheng-Han Kuo, C. França Marcondes Junior, Hélio Afonso Ghizoni Teive, and Orlando Graziani Povoas Barsottini. "Current concepts in the treatment of hereditary ataxias." Arquivos de Neuro-Psiquiatria 74, no. 3 (March 2016): 244–52. http://dx.doi.org/10.1590/0004-282x20160038.
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ABSTRACT Hereditary ataxias (HA) represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.
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Bolus, Harris, Kassi Crocker, Grace Boekhoff-Falk, and Stanislava Chtarbanova. "Modeling Neurodegenerative Disorders in Drosophila melanogaster." International Journal of Molecular Sciences 21, no. 9 (April 26, 2020): 3055. http://dx.doi.org/10.3390/ijms21093055.
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Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders.
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Baron, M., A. P. Kudin, and W. S. Kunz. "Mitochondrial dysfunction in neurodegenerative disorders." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1228–31. http://dx.doi.org/10.1042/bst0351228.
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There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative disorders, such as Morbus Parkinson, FRDA (Friedreich's ataxia), ALS (amyotrophic lateral sclerosis), and temporal lobe epilepsy with Ammon's horn sclerosis. This evidence includes the direct genetic evidence of pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe epilepsy with Ammon's horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative disorders including ALS and temporal lobe epilepsy with Ammon's horn sclerosis. In the present study, we critically review the available data.
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La Rosa, Piergiorgio, Sara Petrillo, Maria Teresa Fiorenza, Enrico Silvio Bertini, and Fiorella Piemonte. "Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease." Biomolecules 10, no. 11 (November 13, 2020): 1551. http://dx.doi.org/10.3390/biom10111551.
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Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.
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Esteras, Noemí, Albena T. Dinkova-Kostova, and Andrey Y. Abramov. "Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function." Biological Chemistry 397, no. 5 (May 1, 2016): 383–400. http://dx.doi.org/10.1515/hsz-2015-0295.
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Abstract The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.
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Ghosh, Arijit, Sangheeta Bhattacharjee, Srijita Paul Chowdhuri, Abhik Mallick, Ishita Rehman, Sudipta Basu, and Benu Brata Das. "SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy." Science Advances 5, no. 11 (November 2019): eaax9778. http://dx.doi.org/10.1126/sciadv.aax9778.
Full textAbstract:
A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 hydrolyzes the phosphodiester bond between DNA 3′-end and a tyrosyl moiety within trapped topoisomerase I (Top1)-DNA covalent complexes (Top1cc). TDP1 is critical for mitochondrial DNA (mtDNA) repair; however, the role of mitochondria remains largely unknown for the etiology of SCAN1. We demonstrate that mitochondria in cells expressing SCAN1-TDP1 (TDP1H493R) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1H493R-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1H493R-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1H493R prompts PTEN-induced kinase 1–dependent mitophagy to eliminate dysfunctional mitochondria. SCAN1-TDP1 in mitochondria creates a pathological state that allows neurons to turn on mitophagy to rescue fit mitochondria as a mechanism of survival.
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Ashley, Claire N., Kelly D. Hoang, David R. Lynch, Susan L. Perlman, and Bernard L. Maria. "Childhood Ataxia." Journal of Child Neurology 27, no. 9 (August 1, 2012): 1095–120. http://dx.doi.org/10.1177/0883073812448840.
Full textAbstract:
Childhood ataxia is characterized by impaired balance and coordination primarily because of cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; and (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.
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Fomicheva, E. I., R. P. Myasnikov, Y. A. Selivyorstov, S. N. Illarioshkin, E. L. Dadali, and O. M. Drapkina. "Cardiomyopathy of Friedreich's Disease. Modern Methods of Diagnostic." Rational Pharmacotherapy in Cardiology 17, no. 1 (March 3, 2021): 105–10. http://dx.doi.org/10.20996/1819-6446-2021-01-05.
Full textAbstract:
Friedreich's disease is a hereditary neurodegenerative multiple organ disease, primarily affecting the most energy-dependent tissues (cells of the nervous system, myocardium, pancreas), the lesion of which is characterized by progressive ataxia, dysarthria, dysphagia, oculomotor disorders, loss of deep tendon reflexes, pyramid signs, diabetes mellitus, visual impairment. Friedreich's ataxia is the most common of all hereditary ataxias; nevertheless, this disease is considered orphan. By its pathogenesis, Friedreich's disease is mitochondrial ataxia, caused by a deficiency in the transcription of the FXN gene, leading to a decrease in the synthesis of the frataxin protein. Frataxin is a protein associated with the inner mitochondrial membrane, which in turn is involved in the formation of iron-sulfur clusters, the lack of which leads to a decrease in the production of mitochondrial ATP, an increase in the level of mitochondrial iron and oxidative stress. The basis of the clinical picture of Friedreich's disease is ataxia of a mixed (sensitive and cerebellar) nature. The steady and gradual progression of neurological symptoms significantly affects the quality of life of patients and is most often the leading reason for seeking medical attention. However, the prognosis is primarily due to the involvement of cardiac tissue in the pathological process. The main causes of death in patients with Friedreich's ataxia are severe heart failure and sudden cardiac death due to cardiomyopathy. The overwhelming majority of foreign and domestic publications on Friedreich's ataxia are devoted to the neurological manifestations of this disease, and little attention is paid to this problem in the cardiological scientific and practical society. The purpose of this review is to provide up-to-date information on modern methods of diagnosing myocardial damage at various stages of Friedreich's disease.
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Parvez, Md Sorwer Alam, and Gen Ohtsuki. "Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology." Brain Sciences 12, no. 3 (March 10, 2022): 367. http://dx.doi.org/10.3390/brainsci12030367.
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The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. In our animal model of the acute inflammation of the cerebellar cortex, animals did not show any ataxia but hyperexcitability in the cerebellar cortex and depression-like behaviors. In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca2+-activated K+ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. In this review, we discuss the hypothesized scenario concerning the emergence of cerebellar ataxia. First, compared with genetically induced cerebellar ataxias, we introduce infection and inflammation in the cerebellum via aberrant immunity and glial responses. Especially, we focus on infections with cytomegalovirus, influenza virus, dengue virus, and SARS-CoV-2, potential relevance to mitochondrial DNA, and autoimmunity in infection. Second, we review neurophysiological modulation (intrinsic excitability, excitatory, and inhibitory synaptic transmission) by inflammatory mediators and aberrant immunity. Next, we discuss the cerebellar circuit dysfunction (presumably, via maintaining the homeostatic property). Lastly, we propose the mechanism of the cerebellar ataxia and possible treatments for the ataxia in the cerebellar inflammation.
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Vrettou, Sofia, and Brunhilde Wirth. "S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases." International Journal of Molecular Sciences 23, no. 24 (December 13, 2022): 15849. http://dx.doi.org/10.3390/ijms232415849.
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Redox post-translational modifications are derived from fluctuations in the redox potential and modulate protein function, localization, activity and structure. Amongst the oxidative reversible modifications, the S-glutathionylation of proteins was the first to be characterized as a post-translational modification, which primarily protects proteins from irreversible oxidation. However, a growing body of evidence suggests that S-glutathionylation plays a key role in core cell processes, particularly in mitochondria, which are the main source of reactive oxygen species. S-nitrosylation, another post-translational modification, was identified >150 years ago, but it was re-introduced as a prototype cell-signaling mechanism only recently, one that tightly regulates core processes within the cell’s sub-compartments, especially in mitochondria. S-glutathionylation and S-nitrosylation are modulated by fluctuations in reactive oxygen and nitrogen species and, in turn, orchestrate mitochondrial bioenergetics machinery, morphology, nutrients metabolism and apoptosis. In many neurodegenerative disorders, mitochondria dysfunction and oxidative/nitrosative stresses trigger or exacerbate their pathologies. Despite the substantial amount of research for most of these disorders, there are no successful treatments, while antioxidant supplementation failed in the majority of clinical trials. Herein, we discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Friedreich’s ataxia.
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Apolloni, Savina, Martina Milani, and Nadia D’Ambrosi. "Neuroinflammation in Friedreich’s Ataxia." International Journal of Molecular Sciences 23, no. 11 (June 4, 2022): 6297. http://dx.doi.org/10.3390/ijms23116297.
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Friedreich’s ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron−sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.
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Vicente-Acosta, Andrés, Alfredo Giménez-Cassina, Javier Díaz-Nido, and Frida Loria. "THE SONIC HEDGEHOG AGONIST SAG ATTENUATES MITOCHONDRIAL DYSFUNCTION AND DECREASES THE NEUROTOXOCITY INDUCED BY FRATAXIN-DEFICIENT ASTROCYTES." IBJ Plus 1, s5 (June 3, 2022): 47. http://dx.doi.org/10.24217/2531-0151.22v1s5.00047.
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Friedreich’s ataxia (FRDA) is predominantly a neurodegenerative disease caused by the deficiency of a protein called frataxin (FXN). Although the main pathological alterations are observed in neurons, it is becoming clear that other non-neuronal cells such as astrocytes may be actively involved in the neurodegenerative process associated with the disease. Depending on the stimuli they respond to, astrocytes acquire different activation states in a process called astrogliosis. Neuroinflammatory stimuli induce the formation of A1 reactive astrocytes, which upregulate proinflammatory genes, being harmful for neurons. A1 astrocytes have been detected in post-mortem tissue of patients with different neurodegenerative disorders, being hypothesized that they might have deleterious effects on neurons, exacerbating the neurodegenerative process. Recent studies have demonstrated positive effects of Sonic Hedgehog (SHH) agonists in astrocyte viability and proliferation, astrocyte-mediated neuroprotection, and also positive effects in mitochondrial activity and dynamics. As mitochondrial changes are important components in the etiology of neurodegenerative disorders, the influence of SHH agonists in mitochondrial physiology could be of therapeutic relevance. In this work, we have thoroughly characterized astrocyte reactivity phenotype and mitochondrial status of FXN-deficient human astrocytes, evaluating as well the effect of SHH agonists on astrocyte reactivity, viability, and function. We used an in vitro model based on a short hairpin RNA packaged in a lentiviral vector, which allowed us to decrease FXN levels in human cortical astrocytes, to similar levels as those observed in FRDA patients, and found that FXN-deficient cells had less cell viability and higher expression of several A1 reactive astrocyte markers, than control cells. Both phenomena were prevented by a chronic treatment with the smoothened agonist (SAG), a SHH signaling agonist. Moreover, FXN-deficient astrocytes showed defects in mitochondrial function and dynamics, which were partially rescued by SAG. Regarding the possible neuroprotective effects of SHH agonists, previous results showed that FXN-deficient astrocytes are able to induce neurodegeneration, and we have observed that the chronic treatment with SAG attenuated the neurotoxicity triggered by the treatment of mouse cortical neurons with conditioned medium of FXN-deficient astrocytes. Overall, our results suggest that the treatment of FXN-deficient astrocytes with a SHH agonist like SAG, could be used as a possible target to reduce FRDA-associated neurodegeneration.
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Boddaert, Nathalie, Kim Hanh Le Quan Sang, Agnès Rötig, Anne Leroy-Willig, Serge Gallet, Francis Brunelle, Daniel Sidi, Jean-Christophe Thalabard, Arnold Munnich, and Z. Ioav Cabantchik. "Selective iron chelation in Friedreich ataxia: biologic and clinical implications." Blood 110, no. 1 (July 1, 2007): 401–8. http://dx.doi.org/10.1182/blood-2006-12-065433.
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Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membrane-permeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with age-matched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s−1 (± 1.6 s−1) to 15.7 s−1 (± 0.7 s−1; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r = 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neuropathy and ataxic gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and hematologic disorders.
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Murtinheira, Fernanda, Mafalda Migueis, Ricardo Letra-Vilela, Mickael Diallo, Andrea Quezada, Cláudia A. Valente, Abel Oliva, Carmen Rodriguez, Vanesa Martin, and Federico Herrera. "Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments." Cells 11, no. 2 (January 16, 2022): 299. http://dx.doi.org/10.3390/cells11020299.
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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.
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Reddy, P. Hemachandra. "Role of Mitochondria in Neurodegenerative Diseases: Mitochondria as a Therapeutic Target in Alzheimer's Disease." CNS Spectrums 14, S7 (August 2009): 8–13. http://dx.doi.org/10.1017/s1092852900024901.
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A growing body of evidence suggests that mitochondrial abnormalities are involved in aging and in age-related neurodegenerative diseases as well as cancer, diabetes, and several other diseases known to be affected by mitochondria. Causal factors for most age-related neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA)—are largely unknown. Genetic defects are reported to cause a small number of neurodegenerative diseases (Slide 1), but cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. However, based on several cellular, molecular, and animal model studies of Alzheimer's disease, Parkinson's disease, ALS, FRDA, cancer, and diabetes, aging may play a large role in cell death in these diseases. Age-dependent, mitochondrially-generated reactive oxygen species (ROS) have been identified as important factors responsible for disease progression and cell death, particularly in late-onset diseases, in which genetic mutations are not causal factors.
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Sliwa, Dominika, Julien Dairou, Jean-Michel Camadro, and Renata Santos. "Inactivation of mitochondrial aspartate aminotransferase contributes to the respiratory deficit of yeast frataxin-deficient cells." Biochemical Journal 441, no. 3 (January 16, 2012): 945–53. http://dx.doi.org/10.1042/bj20111574.
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Friedreich's ataxia is a hereditary neurodegenerative disease caused by reduced expression of mitochondrial frataxin. Frataxin deficiency causes impairment in respiratory capacity, disruption of iron homoeostasis and hypersensitivity to oxidants. Although the redox properties of NAD (NAD+ and NADH) are essential for energy metabolism, only few results are available concerning homoeostasis of these nucleotides in frataxin-deficient cells. In the present study, we show that the malate–aspartate NADH shuttle is impaired in Saccharomyces cerevisiae frataxin-deficient cells (Δyfh1) due to decreased activity of cytosolic and mitochondrial isoforms of malate dehydrogenase and to complete inactivation of the mitochondrial aspartate aminotransferase (Aat1). A considerable decrease in the amount of mitochondrial acetylated proteins was observed in the Δyfh1 mutant compared with wild-type. Aat1 is acetylated in wild-type mitochondria and deacetylated in Δyfh1 mitochondria suggesting that inactivation could be due to this post-translational modification. Mutants deficient in iron–sulfur cluster assembly or lacking mitochondrial DNA also showed decreased activity of Aat1, suggesting that Aat1 inactivation was a secondary phenotype in Δyfh1 cells. Interestingly, deletion of the AAT1 gene in a wild-type strain caused respiratory deficiency and disruption of iron homoeostasis without any sensitivity to oxidative stress. Our results show that secondary inactivation of Aat1 contributes to the amplification of the respiratory defect observed in Δyfh1 cells. Further implication of mitochondrial protein deacetylation in the physiology of frataxin-deficient cells is anticipated.
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Ocana-Santero, Gabriel, Javier Díaz-Nido, and Saúl Herranz-Martín. "Future Prospects of Gene Therapy for Friedreich’s Ataxia." International Journal of Molecular Sciences 22, no. 4 (February 11, 2021): 1815. http://dx.doi.org/10.3390/ijms22041815.
Full textAbstract:
Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.
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Alwatban, Saud Mohammed, Haifa Alfaraidi, Majid Alfadhel, and Angham N. Almutair. "Case Report and Literature Review: Homozygous DNAJC3 Mutation in a Saudi Family Causing Maturity Onset Diabetes of the Young (MODY), Hypothyroidism, Short Stature, Neurodegeneration, and Hearing Loss." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A696—A697. http://dx.doi.org/10.1210/jendso/bvab048.1419.
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Abstract Introduction: Monogenic diabetes results from a mutation in single gene, predominantly inherited and typically affects the young. DNAJC3 acts in attenuating endoplasmic reticulum stress and is found in abundance in pancreatic tissue. Clinical Case: We report a homozygous DNAJC3 mutation in two siblings of a consanguineous Saudi family. A 3-year boy presented with short stature and thyroid nodule; lab findings confirmed hypothyroidism, with TSH 27.8 and FT4 6.7 (n: TSH:0.35-4.94 mIU/L, FT4:9.0-19 pmol/L). Subsequently, L-thyroxine was started. GH stimulation test was normal. He was severely short; 80.5 cm (< 1 percentile, -3.79 SD). The patient developed sensorineural hearing loss (SNHL) at 6 years. He had low intellectual function and weak school performance. GH treatment was postponed to age 9 due to strong family history of DM. At that point, the patient developed progressive ataxic gait, for which he had muscle biopsy that excluded mitochondrial disease and workup for multiple sclerosis, which was excluded. Brain and spine MRI showed prominent neurodegeneration in subcortical white matter. At age 11, the patient developed DM, 4 years after GH treatment initiation. DM autoimmune markers were negative on multiple occasions. Lifestyle modification was initiated but soon required basal and bolus insulin therapy. Whole exome sequencing revealed homozygous DNAJC3 mutation, which explained his clinical presentation. At age of 17, adult height was 141 cm (Z-score: -5.87). His older brother had similar history discovered retrospectively but did not develop neurodegeneration or ataxia from the same DNAJC3 mutation. Literature Review: Literature review revealed six individuals with homozygous DNAJC3 mutation. All patients developed DM, with onset ranging from 11 to 19 years, highly suggestive of MODY. Other endocrine manifestations included short stature, and hypothyroidism due to primary etiology; in view of elevated TSH levels, vs. being secondary, as suggested by the authors. All patients had mitochondrial disease workups and was excluded. Variable neurodegeneration degrees are described; SNHL, progressive ataxia, sensorimotor neuropathy, and cognitive deficits. MRI findings showed atrophy of cerebellum, brainstem, cervical spinal cord, and hyperintense T2 lesions typical of neurodegeneration. Conclusion: Homozygous DNAJC3 gene mutation fits MODY criteria, we propose recognizing it as one of the known MODY gene mutations. Hypothyroidism is due to primary etiology, evident by TSH spikes. Physicians evaluating mitochondrial disease in patients with a constellation of SNHL, DM, hypothyroidism, neurodegeneration, and short stature should suspect DNAJC3 as one differential diagnosis. GH treatment must be initiated cautiously, with close monitoring due to its known diabetogenic effect, especially in DNAJC3 mutations, defective endoplasmic stress attenuation mechanism.
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Dorn, Gerald W., and Xiawei Dang. "Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases." Cells 11, no. 6 (March 19, 2022): 1049. http://dx.doi.org/10.3390/cells11061049.
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Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot–Marie–Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich’s ataxia, dominant optic atrophy, and Alzheimer’s, Huntington’s, and Parkinson’s diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.
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Perlman, Susan. "Emerging Therapies in Friedreich's Ataxia: A Review." Neurology 18, no. 1 (2022): 32. http://dx.doi.org/10.17925/usn.2022.18.1.32.
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Friedreich's ataxia (FRDA) is an inherited, neurodegenerative disease that typically presents in childhood and results in progressive gait and limb ataxia, with the extraneural features of hypertrophic cardiomyopathy, diabetes and scoliosis. The genetic defect results in a deficiency of frataxin protein, which is important for mitochondrial function, especially in the brain and heart. Drug development has approached FRDA through pathways addressing oxidative stress, mitochondrial dysfunction, frataxin protein deficiency and DNA transcriptional deficiency, paving the way for the first disease-modifying drugs for FRDA.
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Agrò, Mauro, and Javier Díaz-Nido. "Effect of Mitochondrial and Cytosolic FXN Isoform Expression on Mitochondrial Dynamics and Metabolism." International Journal of Molecular Sciences 21, no. 21 (November 4, 2020): 8251. http://dx.doi.org/10.3390/ijms21218251.
Full textAbstract:
Friedreich’s ataxia (FRDA) is a neurodegenerative disease caused by recessive mutations in the frataxin gene that lead to a deficiency of the mitochondrial frataxin (FXN) protein. Alternative forms of frataxin have been described, with different cellular localization and tissue distribution, including a cerebellum-specific cytosolic isoform called FXN II. Here, we explored the functional roles of FXN II in comparison to the mitochondrial FXN I isoform, highlighting the existence of potential cross-talk between cellular compartments. To achieve this, we transduced two human cell lines of patient and healthy subjects with lentiviral vectors overexpressing the mitochondrial or the cytosolic FXN isoforms and studied their effect on the mitochondrial network and metabolism. We confirmed the cytosolic localization of FXN isoform II in our in vitro models. Interestingly, both cytosolic and mitochondrial isoforms have an effect on mitochondrial dynamics, affecting different parameters. Accordingly, increases of mitochondrial respiration were detected after transduction with FXN I or FXN II in both cellular models. Together, these results point to the existence of a potential cross-talk mechanism between the cytosol and mitochondria, mediated by FXN isoforms. A more thorough knowledge of the mechanisms of action behind the extra-mitochondrial FXN II isoform could prove useful in unraveling FRDA physiopathology.
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Chiapparini, Luisa, and Marco Moscatelli. "Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases." Applied Sciences 11, no. 18 (September 14, 2021): 8522. http://dx.doi.org/10.3390/app11188522.
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In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening.
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Stendel, Claudia, Christiane Neuhofer, Elisa Floride, Shi Yuqing, Rebecca D. Ganetzky, Joohyun Park, Peter Freisinger, et al. "Delineating MT-ATP6-associated disease." Neurology Genetics 6, no. 1 (January 13, 2020): e393. http://dx.doi.org/10.1212/nxg.0000000000000393.
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ObjectiveTo delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations in a large international cohort.MethodsWe analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.ResultsWe identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic MT-ATP6 mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%–100%) and unaffected individuals (mean 73%, range 20%–100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).ConclusionsIn this currently largest series of patients with mitochondrial MT-ATP6 mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include MT-ATP6 mutations in the differential diagnosis of both ataxias and neuropathies.
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Nuñez, Marco, and Pedro Chana-Cuevas. "New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases." Pharmaceuticals 11, no. 4 (October 19, 2018): 109. http://dx.doi.org/10.3390/ph11040109.
Full textAbstract:
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.
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Turchi, Riccardo, Raffaella Faraonio, Daniele Lettieri-Barbato, and Katia Aquilano. "An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia." Biomolecules 10, no. 11 (October 28, 2020): 1489. http://dx.doi.org/10.3390/biom10111489.
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Background: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.
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Li, Xinlu (Crystal). "Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): a once obscure neurodegenerative disease with increasing significance for neurological research." McGill Science Undergraduate Research Journal 8, no. 1 (March 31, 2013): 69–74. http://dx.doi.org/10.26443/msurj.v8i1.114.
Full textAbstract:
Background: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare cerebellar ataxia occurring in the Charlevoix-Saguenay population in Quebec with high incidence as a result of founder effects. Following the discovery of the gene responsible for the disease, many other patient groups have been identified worldwide and the characterization of the gene product, sacsin, has unveiled similarities between the pathogenic mechanism of ARSACS and those of other major neurodegenerative disease.
Summary: The core symptoms of ARSACS consist of a triad of early-onset cerebellar ataxia, peripheral neuropathy and spasticity, which is accounted by degeneration of Purkinje neurons. The gene responsible for the disease is located on chromosome 13q11 and encodes for the chaperone sacsin. Drp-1, a GTPase crucial for regulating mitochondrial fission/fusion dynamics, has been identified as a potential substrate of sacsin, suggesting a link between the pathogenic mechanisms of ARSACS and prevalent neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases.
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Hartley, Jessica N., Frances A. Booth, Marc R. Del Bigio, and Aizeddin A. Mhanni. "Novel Autosomal Recessivec10orf2Mutations Causing Infantile-Onset Spinocerebellar Ataxia." Case Reports in Pediatrics 2012 (2012): 1–4. http://dx.doi.org/10.1155/2012/303096.
Full textAbstract:
Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene,c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in thec10orf2gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.
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Tabrizi, S. J., and A. H. V. Schapira. "Secondary abnormalities of mitochondrial DNA associated with neurodegeneration." Biochemical Society Symposia 66 (September 1, 1999): 99–110. http://dx.doi.org/10.1042/bss0660099.
Full textAbstract:
The central nervous system has a particularly high energy requirement, thus making it very susceptible to defects in mitochondrial function. A number of neurodegenerative diseases, in particular Parkinson's disease (PD), Huntington's disease (HD) and Friedreich's ataxia (FRDA), are associated with mitochondrial dysfunction. The identification of a mitochondrial complex-I defect in PD provides a link between toxin models of the disease, and clues to the pathogenesis of idiopathic PD. We have undertaken genomic transplantation studies involving the transfer of mitochondrial DNA (mtDNA) from PD patients with a complex-I defect to a novel nuclear background. Histochemical, immunohistochemical and functional analysis of the resulting cybrids all showed a pattern in the PD clones indicative of a mtDNA mutation. There is good evidence for the involvement of defective energy metabolism and excitotoxicity in the aetiology of HD. We, and others, have shown a severe deficiency of complex II/III confined to the striatum that mimics the toxin-induced animal models of HD. There is also a milder defect in complex IV in the caudate. The tricarboxylic acid cycle enzyme aconitase is particularly sensitive to inhibition by peroxynitrite and superoxide radicals. We have found this enzyme to be severely decreased in HD caudate, putamen and cortex in a pattern that parallels the severity of neuronal loss seen. We propose a scheme for the role of nitric oxide, free radicals and excitotoxicity in the pathogenesis of HD. FRDA is caused by an expanded GAA repeat in intron 1 of the X25 gene encoding a protein called frataxin. Frataxin is widely expressed and is a mitochondrial protein, although its function is unknown. We have found abnormal magnetic resonance spectroscopy in the skeletal muscle of FRDA patients, which parallels our biochemical findings of reduced complexes I-III in patients' heart and skeletal muscle. There is also reduced aconitase activity in these areas. Increased iron deposition was seen in patients' tissues in a pattern consistent with a mitochondrial location. The mitochondrial iron accumulation, defective respiratory chain activity and aconitase dysfunction suggest that frataxin may be involved in mitochondrial iron regulation. There is also evidence that oxidative stress contributes to cellular toxicity.
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Seco-Cervera, Marta, Pilar González-Cabo, Federico Pallardó, Carlos Romá-Mateo, and José García-Giménez. "Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia." Antioxidants 9, no. 12 (December 10, 2020): 1257. http://dx.doi.org/10.3390/antiox9121257.
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The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.
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Cotticelli, M. Grazia, Lynn Rasmussen, Nicole L. Kushner, Sara McKellip, Melinda Ingrum Sosa, Anna Manouvakhova, Shuang Feng, et al. "Primary and Secondary Drug Screening Assays for Friedreich Ataxia." Journal of Biomolecular Screening 17, no. 3 (November 15, 2011): 303–13. http://dx.doi.org/10.1177/1087057111427949.
Full textAbstract:
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix for the assembly of iron–sulfur clusters (ISCs), which are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain (ETC). Decreased expression of frataxin or the yeast frataxin orthologue, Yfh1p, is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. Using yeast depleted of Yfh1p, a high-throughput screening (HTS) assay was developed in which mitochondrial function was monitored by reduction of the tetrazolium dye WST-1 in a growth medium with a respiration-only carbon source. Of 101 200 compounds screened, 302 were identified that effectively rescue mitochondrial function. To confirm activities in mammalian cells and begin understanding mechanisms of action, secondary screening assays were developed using murine C2C12 cells and yeast mutants lacking specific complexes of the ETC, respectively. The compounds identified in this study have potential relevance for other neurodegenerative disorders associated with mitochondrial dysfunction, such as Parkinson disease.
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Palombo, Flavia, Chiara La Morgia, Claudio Fiorini, Leonardo Caporali, Maria Lucia Valentino, Vincenzo Donadio, Rocco Liguori, and Valerio Carelli. "A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia." Neurology Genetics 8, no. 5 (August 8, 2022): e200004. http://dx.doi.org/10.1212/nxg.0000000000200004.
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Background and ObjectivesTo date, approximately 20 heterozygous mainly loss-of-function variants in KCND3 have been associated with spinocerebellar ataxia (SCA) type 19 and 22, a clinically heterogeneous group of neurodegenerative disorders. We aimed at reporting the second patients with the V374A KCND3 mutation from an independent family, confirming its pathogenic role.MethodsWe describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing.ResultsThis male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121T>C [p.V374A] mutation in KCND3.DiscussionThis report consolidates the pathogenicity of the V374A KCND3 mutation and suggests that the ataxic paroxysmal exacerbations are not a key phenotypic feature of this mutation.
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Bagaria, Jaya, Eva Bagyinszky, and Seong Soo A. An. "Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration." International Journal of Molecular Sciences 23, no. 1 (January 4, 2022): 552. http://dx.doi.org/10.3390/ijms23010552.
Full textAbstract:
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.
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La Rosa, Piergiorgio, Enrico Silvio Bertini, and Fiorella Piemonte. "The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia." International Journal of Molecular Sciences 21, no. 3 (January 30, 2020): 916. http://dx.doi.org/10.3390/ijms21030916.
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Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.
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Doni, Davide, Marta Meggiolaro, Javier Santos, Gérard Audran, Sylvain R. A. Marque, Paola Costantini, Marco Bortolus, and Donatella Carbonera. "A Combined Spectroscopic and In Silico Approach to Evaluate the Interaction of Human Frataxin with Mitochondrial Superoxide Dismutase." Biomedicines 9, no. 12 (November 25, 2021): 1763. http://dx.doi.org/10.3390/biomedicines9121763.
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Frataxin (FXN) is a highly conserved mitochondrial protein whose deficiency causes Friedreich’s ataxia, a neurodegenerative disease. The precise physiological function of FXN is still unclear; however, there is experimental evidence that the protein is involved in biosynthetic iron–sulfur cluster machinery, redox imbalance, and iron homeostasis. FXN is synthesized in the cytosol and imported into the mitochondria, where it is proteolytically cleaved to the mature form. Its involvement in the redox imbalance suggests that FXN could interact with mitochondrial superoxide dismutase (SOD2), a key enzyme in antioxidant cellular defense. In this work, we use site-directed spin labelling coupled to electron paramagnetic resonance spectroscopy (SDSL-EPR) and fluorescence quenching experiments to investigate the interaction between human FXN and SOD2 in vitro. Spectroscopic data are combined with rigid body protein–protein docking to assess the potential structure of the FXN-SOD2 complex, which leaves the metal binding region of FXN accessible to the solvent. We provide evidence that human FXN interacts with human SOD2 in vitro and that the complex is in fast exchange. This interaction could be relevant during the assembly of iron-sulfur (FeS) clusters and/or their incorporation in proteins when FeS clusters are potentially susceptible to attacks by reactive oxygen species.