Journal articles on the topic 'Ataxia, SCA28, Neurodegeneration, mitochondria'
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1
Tulli, Susanna, Andrea Del Bondio, Valentina Baderna, Davide Mazza, Franca Codazzi, Tyler Mark Pierson, Alessandro Ambrosi, et al. "Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation." Journal of Medical Genetics 56, no. 8 (March 25, 2019): 499–511. http://dx.doi.org/10.1136/jmedgenet-2018-105766.
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BackgroundSpinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.MethodsWe derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/− HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2−/− murine fibroblasts.ResultsWe found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.ConclusionOur data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/− cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.
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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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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.
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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.
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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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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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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.
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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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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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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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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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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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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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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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Almalki, Waleed Hassan, Shahad Abdullah Alshamrani, Refal Essam Fagieha, Nura Hamad Bin Hallabi, Lamya Abdullah Almatrafi, and Taif Abdullah Alahmadi. "A review on neurodegenerative diseases associated with oxidative stress and mitochondria." International journal of health sciences, April 23, 2022, 5665–78. http://dx.doi.org/10.53730/ijhs.v6ns1.6130.
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Alzheimer's disease, Parkinson's disease, and other neurological diseases afflict people of all ages. Neuronal loss and cognitive dysfunction are common symptoms of these disorders. Overproduction of reactive oxygen species has been demonstrated to aggravate disease progression in previous investigations (ROS). Because of the large quantities of polyunsaturated fatty acids in their membranes and their fast oxygen consumption rate, neurons are especially susceptible to oxidative damage. The molecular aetiology of neurodegeneration produced by changes in redox balance has not yet been established. New antioxidants have shown considerable potential in modifying disease characteristics. For the treatment of Alzheimer's disease and other neurodegenerative illnesses such as Parkinson's disease, ALS and spinocerebellar ataxia and Huntington's disease, antioxidant-based therapies are examined extensively in the literature.
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Weng, Liwei, Laurent Laboureur, Qingqing Wang, Lili Guo, Peining Xu, Leah Gottlieb, David R. Lynch, Clementina Mesaros, and Ian A. Blair. "Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia." Scientific Reports 10, no. 1 (September 25, 2020). http://dx.doi.org/10.1038/s41598-020-72884-w.
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Abstract Mature frataxin is essential for the assembly of iron–sulfur cluster proteins including a number of mitochondrial enzymes. Reduced levels of mature frataxin (81-20) in human subjects caused by the genetic disease Friedreich’s ataxia results in decreased mitochondrial function, neurodegeneration, and cardiomyopathy. Numerous studies of mitochondrial dysfunction have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, we have discovered that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.
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Toth-Bencsik, Renata, Peter Balicza, Edina Timea Varga, Andras Lengyel, Gabor Rudas, Aniko Gal, and Maria Judit Molnar. "New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family." Frontiers in Genetics 12 (June 8, 2021). http://dx.doi.org/10.3389/fgene.2021.628904.
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IntroductionPhospholipase A2-associated Neurodegeneration (PLAN) is a group of neurodegenerative diseases associated with the alterations of PLA2G6. Some phenotype-genotype association are well known but there is no clear explanation why some cases can be classified into distinct subgroups, while others follow a continuous clinical spectrum.MethodsLong-term neurological, and psychiatric follow-up, neuropathological, radiological, and genetic examinations, were performed in three affected girls and their family.ResultsTwo 24-years old twins and their 22-years old sister harbored the p.P622S, and p.R600W mutation in PLA2G6. The age of onset and the most prominent presenting symptoms (gaze palsy, ataxia, dystonia, psychomotor regression indicated atypical neuroaxonal dystrophy (ANAD), however, optic atrophy, severe tetraparesis would fit into infantile neuroaxonal dystrophy (INAD). All siblings had hyperintensity in the globi pallidi and substantiae nigrae which is reported in ANAD, whereas it is considered a later neuroradiological marker in INAD. The slow progression, rigidity, bradykinesis, and the prominent psychiatric symptoms indicate PLA2G6-related dystonia-parkinsonism. Abnormal mitochondria, lipid accumulation and axonal spheroids were observed in the muscle and nerve tissue. Brain deposition appeared 6 years following the initial cerebellar atrophy. Mild MRI alterations were detected in the asymptomatic carrier parents.ConclusionThe colorful clinical symptoms, the slightly discordant phenotype, and the neuroimaging data in the family supports the view that despite the distinct definition of age-related phenotypes in PLAN, these are not strict disease categories, but rather a continuous phenotypic spectrum. The mild MRI alterations of the parents and the family history suggest that even heterozygous pathogenic variants might be associated with clinical symptoms, although systematic study is needed to prove this.