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Journal articles on the topic 'Spinal muscular atrophy; Neurodegenerative'
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1
Agrawal, Priyanka, and Pradnya Kulkarni. "An Unusual Presentation of Bilateral Vocal Fold Paralysis due to Spinal Muscular Atrophy." International Journal of Phonosurgery & Laryngology 4, no. 1 (2014): 27–29. http://dx.doi.org/10.5005/jp-journals-10023-1075.
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ABSTRACT Background Spinal muscular atrophy is a rare autosomal recessive neurodegenerative disorder. We report a case of 62-year-old female of spinal muscular atrophy presenting with bilateral vocal fold paralysis, her diagnosis and management. Objective Case report of a case of spinal muscular atrophy presenting with bilateral vocal fold paralysis. Conclusion Spinomuscular atrophy though rarely associated with laryngeal symptoms should be kept in mind as a possible etiology of bilateral vocal fold paralysis. The surgical decision and the postoperative sequeale will be affected due to the presence of this disease and thus a high index of suspicion is required. How to cite this article Nerurkar NK, Deshmukh S, Agrawal P, Kulkarni P. An Unusual Presentation of Bilateral Vocal Fold Paralysis due to Spinal Muscular Atrophy. Int J Phonosurg Laryngol 2014;4(1):27-29.
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Bennett, C. Frank, Adrian R. Krainer, and Don W. Cleveland. "Antisense Oligonucleotide Therapies for Neurodegenerative Diseases." Annual Review of Neuroscience 42, no. 1 (July 8, 2019): 385–406. http://dx.doi.org/10.1146/annurev-neuro-070918-050501.
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Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.
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Teoh, Hooi Ling, Kate Carey, Hugo Sampaio, David Mowat, Tony Roscioli, and Michelle Farrar. "Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy." Neural Plasticity 2017 (2017): 1–22. http://dx.doi.org/10.1155/2017/6509493.
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Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.
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Brooks, Brian P., and Kenneth H. Fischbeck. "Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease." Trends in Neurosciences 18, no. 10 (October 1995): 459–61. http://dx.doi.org/10.1016/0166-2236(95)94497-s.
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Gavrichenko, A. V., A. I. Kulyakhtin, A. A. Yakovlev, M. G. Sokolova, A. G. Smochilin, V. S. Fedorova, and R. A. Gapeshin. "Spinal and bulbar muscular atrophy (Kennedy’s disease): case description." Scientific Notes of the Pavlov University 26, no. 3 (February 4, 2020): 86–93. http://dx.doi.org/10.24884/1607-4181-2019-26-3-86-93.
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Kennedy’s X-linked spinal and bulbar muscular atrophy is a rare hereditary lower motoneuron neurodegenerative disease, which is based on the genetic defect of the androgen receptor’s first exon (AR), characterized by an abnormal increase of CAG-repeats. This article describes a clinical case of a patient with complaints about low limb weakness, walking distance shortening to 400–500 meters, coordination disturbances, and moderate polyneuropathy. According to complaints, neurological examination and patient’s family history, a genetic study was performed confirming the proposed diagnosis. Following neurometabolic, vitamin, physical therapy, physiotherapy and acupuncture were performed and the patient’s physical activity increasing and intensity of symptoms reduction was achieved. The article also highlights the features of pathogenesis and the prospects for pathogenetic treatment of this disease.
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James, Rachel, Helena Chaytow, Leire M. Ledahawsky, and Thomas H. Gillingwater. "Revisiting the role of mitochondria in spinal muscular atrophy." Cellular and Molecular Life Sciences 78, no. 10 (April 5, 2021): 4785–804. http://dx.doi.org/10.1007/s00018-021-03819-5.
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AbstractSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor neuron 1 (SMN1) gene. Despite its name, SMN is a ubiquitous protein that functions within and outside the nervous system and has multiple cellular roles in transcription, translation, and proteostatic mechanisms. Encouragingly, several SMN-directed therapies have recently reached the clinic, albeit this has highlighted the increasing need to develop combinatorial therapies for SMA to achieve full clinical efficacy. As a subcellular site of dysfunction in SMA, mitochondria represents a relevant target for a combinatorial therapy. Accordingly, we will discuss our current understanding of mitochondrial dysfunction in SMA, highlighting mitochondrial-based pathways that offer further mechanistic insights into the involvement of mitochondria in SMA. This may ultimately facilitate translational development of targeted mitochondrial therapies for SMA. Due to clinical and mechanistic overlaps, such strategies may also benefit other motor neuron diseases and related neurodegenerative disorders.
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Hoolachan, Joseph M., Emma R. Sutton, and Melissa Bowerman. "Teaching an old drug new tricks: repositioning strategies for spinal muscular atrophy." Future Neurology 14, no. 3 (August 2019): FNL25. http://dx.doi.org/10.2217/fnl-2019-0006.
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Spinal muscular atrophy (SMA) is a childhood disorder caused by loss of the SMN gene. Pathological hallmarks are spinal cord motor neuron death, neuromuscular junction dysfunction and muscle atrophy. The first SMN genetic therapy was recently approved and other SMN-dependent treatments are not far behind. However, not all SMA patients will reap their maximal benefit due to limited accessibility, high costs and differential effects depending on timing of administration and disease severity. The repurposing of commercially available drugs is an interesting strategy to ensure more rapid and less expensive access to new treatments. In this mini-review, we will discuss the potential and relevance of repositioning drugs currently used for neurodegenerative, neuromuscular and muscle disorders for SMA.
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Ahmad, Saif, Kanchan Bhatia, Annapoorna Kannan, and Laxman Gangwani. "Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy." Journal of Experimental Neuroscience 10 (January 2016): JEN.S33122. http://dx.doi.org/10.4137/jen.s33122.
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Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.
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Farrar, Michelle A., Steve Vucic, Heather M. Johnston, and Matthew M. Kiernan. "36. Mechanisms of neurodegeneration in spinal muscular atrophy." Journal of Clinical Neuroscience 17, no. 12 (December 2010): 1621. http://dx.doi.org/10.1016/j.jocn.2010.07.037.
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Sen, Anindya, Takakazu Yokokura, Mark W. Kankel, Douglas N. Dimlich, Jan Manent, Subhabrata Sanyal, and Spyros Artavanis-Tsakonas. "Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling." Journal of Cell Biology 192, no. 3 (February 7, 2011): 481–95. http://dx.doi.org/10.1083/jcb.201004016.
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Spinal muscular atrophy (SMA), a devastating neurodegenerative disorder characterized by motor neuron loss and muscle atrophy, has been linked to mutations in the Survival Motor Neuron (SMN) gene. Based on an SMA model we developed in Drosophila, which displays features that are analogous to the human pathology and vertebrate SMA models, we functionally linked the fibroblast growth factor (FGF) signaling pathway to the Drosophila homologue of SMN, Smn. Here, we characterize this relationship and demonstrate that Smn activity regulates the expression of FGF signaling components and thus FGF signaling. Furthermore, we show that alterations in FGF signaling activity are able to modify the neuromuscular junction defects caused by loss of Smn function and that muscle-specific activation of FGF is sufficient to rescue Smn-associated abnormalities.
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Li, Yang-Jean, Tai-Heng Chen, Yan-Zhang Wu, and Yung-Hao Tseng. "Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy." Nutrients 12, no. 12 (December 16, 2020): 3842. http://dx.doi.org/10.3390/nu12123842.
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Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.
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Lejman, Jan, Grzegorz Zieliński, Piotr Gawda, and Monika Lejman. "Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy." Genes 12, no. 9 (August 28, 2021): 1346. http://dx.doi.org/10.3390/genes12091346.
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It has been estimated that 80% of the pre-mRNA undergoes alternative splicing, which exponentially increases the flow of biological information in cellular processes and can be an attractive therapeutic target. It is a crucial mechanism to increase genetic diversity. Disturbed alternative splicing is observed in many disorders, including neuromuscular diseases and carcinomas. Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. Homozygous deletion in 5q13 (the region coding for the motor neuron survival gene (SMN1)) is responsible for 95% of SMA cases. The nearly identical SMN2 gene does not compensate for SMN loss caused by SMN1 gene mutation due to different splicing of exon 7. A pathologically low level of survival motor neuron protein (SMN) causes degeneration of the anterior horn cells in the spinal cord with associated destruction of α-motor cells and manifested by muscle weakness and loss. Understanding the regulation of the SMN2 pre-mRNA splicing process has allowed for innovative treatment and the introduction of new medicines for SMA. After describing the concept of splicing modulation, this review will cover the progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of SMA using the mechanism of alternative splicing.
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Tsai, Li-Kai. "Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets." Neural Plasticity 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/456478.
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Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of thesurvival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, theSMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.
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Abe, Hiroaki, Reo Inoue, Rikuhei Tsuchida, Kenji Azuma, Kenji Ino, Mitsuru Konishi, Jun Hozumi, and Masahiko Sumitani. "Use of three-dimensional printing of a lumbar skeletal model for intrathecal administration of nusinersen: a brief technical report." Regional Anesthesia & Pain Medicine 45, no. 10 (August 18, 2020): 757–60. http://dx.doi.org/10.1136/rapm-2020-101607.
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Spinal muscular atrophy (SMA) is an autosomal recessive hereditary neurodegenerative disease causing progressive muscle atrophy, weakness and kyphoscoliosis. Nusinersen is a therapeutic agent for SMA that should be administered intrathecally. However, due to severe kyphoscoliosis, lumbar puncture can be challenging. Here, we present our experience of intrathecal administration of nusinersen in an SMA patient with severe kyphoscoliosis using a life-size three-dimensional printing (3D) skeletal model created with 3D printer. With this strategy, we were able to rapidly and safely perform the lumbar puncture.
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Skoretz, Stacey A., May-Sann Yee, and Rosemary Martino. "Complications After Cardiovascular Surgery in a Case of Undiagnosed Spinal-Bulbar Muscular Atrophy (Kennedy Disease)." American Journal of Critical Care 21, no. 2 (March 1, 2012): 139–38. http://dx.doi.org/10.4037/ajcc2012453.
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Neurodegenerative diseases are often associated with life-threatening declines in respiratory and swallowing mechanisms. We report the case of a 70-year-old man who had postoperative dysphagia and respiratory failure that required reintubation after coronary artery bypass surgery. Impairment of the patient’s speech, swallowing, and respiratory mechanisms identified during postoperative clinical and instrumental examinations was suggestive of a neurodegenerative disease. Genetic testing confirmed a diagnosis of spinal-bulbar muscular atrophy (Kennedy disease). This case report aims toLhighlight increased morbidity in patients with undiagnosed neuromuscular disorders in the critical care setting and the benefits of vigilant postoperative monitoring and multidisciplinary involvement throughout the care of complex patients.
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Alaqeel, AM, H. Abou Al-Shaar, RK Shariff, and A. Albakr. "The role of RNA metabolism in neurological diseases." Balkan Journal of Medical Genetics 18, no. 2 (December 1, 2015): 5–14. http://dx.doi.org/10.1515/bjmg-2015-0080.
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Abstract Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy.
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Scoles, Daniel R., Eric V. Minikel, and Stefan M. Pulst. "Antisense oligonucleotides." Neurology Genetics 5, no. 2 (April 2019): e323. http://dx.doi.org/10.1212/nxg.0000000000000323.
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There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.
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Bora-Tatar, Gamze, and Hayat Erdem-Yurter. "Investigations of Curcumin and Resveratrol on Neurite Outgrowth: Perspectives on Spinal Muscular Atrophy." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/709108.
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Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease with progressive muscle weakness and atrophy. SMA is caused by low levels of the Survival of Motor Neuron (SMN) protein, which also leads to neurite outgrowth defects in neuronal cells. Rescue of the outgrowth defect is thought to be a strategy for SMA treatment. Polyphenolic histone deacetylase (HDAC) inhibitors might be good candidates due to their neuritogenic properties. In the present study, it was investigated whether neurite outgrowth defects could be rescued by curcumin and resveratrol, which are SMN-inducing polyphenols, having HDAC inhibition activity. According to our results, although curcumin and resveratrol failed to restore the neurite outgrowth defects, the SMN protein was found to be necessary for the neurite-promoting activity of curcumin in neuron-like PC12 cells.
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Pagliarini, Vittoria, Laura Pelosi, Maria Blaire Bustamante, Annalisa Nobili, Maria Grazia Berardinelli, Marcello D’Amelio, Antonio Musarò, and Claudio Sette. "SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy." Journal of Cell Biology 211, no. 1 (October 5, 2015): 77–90. http://dx.doi.org/10.1083/jcb.201502059.
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Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre–messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3′ splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.
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Lin, Mengsi, Xinyi Hu, Shiyi Chang, Yan Chang, Wenjun Bian, Ruikun Hu, Jing Wang, Qingwen Zhu, and Jiaying Qiu. "Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases." Evidence-Based Complementary and Alternative Medicine 2021 (June 10, 2021): 1–9. http://dx.doi.org/10.1155/2021/6678422.
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Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.
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Rudnicki, Dobrila D., and Russell L. Margolis. "Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy." Expert Reviews in Molecular Medicine 5, no. 21 (August 22, 2003): 1–24. http://dx.doi.org/10.1017/s1462399403006598.
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Repeat-expansion mutations cause 13 autosomal dominant neurodegenerative disorders falling into three groups. Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs) types 1, 2, 3, 7 and 17 are each caused by a CAG repeat expansion that encodes polyglutamine. Convergent lines of evidence demonstrate that neurodegeneration in these diseases is a consequence of the neurotoxic effects of abnormally long stretches of glutamines. How polyglutamine induces neurodegeneration, and why neurodegeneration occurs in only select neuronal populations, remains a matter of intense investigation. SCA6 is caused by a CAG repeat expansion in CACNA1A, a gene that encodes a subunit of the P/Q-type calcium channel. The threshold length at which the repeat causes disease is much shorter than in the other polyglutamine diseases, and neurodegeneration may arise from expansion-induced change of function in the calcium channel. Huntington's disease-like 2 (HDL2) and SCAs 8, 10 and 12 are rare disorders in which the repeats (CAG, CTG or ATTCT) are not in protein-coding regions. Investigation into these diseases is still at an early stage, but it is now reasonable to hypothesise that the net effect of each expansion is to alter gene expression. The different pathogenic mechanisms in these three groups of diseases have important implications for the development of rational therapeutics.
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Wanker, Erich E. "Protein Aggregation and Pathogenesis of Huntingtons Disease: Mechanisms and Correlations." Biological Chemistry 381, no. 9-10 (September 13, 2000): 937–42. http://dx.doi.org/10.1515/bc.2000.114.
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Abstract The formation of insoluble protein aggregates is a hallmark of Huntington's disease (HD) and related neurodegenerative disorders, such as dentatorubral pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA) and the spinocerebellar ataxia (SCA) type 1, 2, 3, 6 and 7. These disorders are caused by an expanded polyglutamine (polyQ) tract in otherwise unrelated proteins. They are characterized by late-onset, selective neuropathology, a pathogenic polyQ threshold and a relationship between polyQ length and disease progression. Thus, molecular models of HD and related glutamine-repeat disorders must account for these characteristic features. During the last three years, considerable effort has been invested in the development of in vitro and in vivo model systems to study the mechanisms of protein aggregation in glutamine-repeat disorders and its potential effects on disease progression and neurodegeneration. A selection of these studies is reviewed here. Furthermore, the correlation between aggregate formation and development of HD is discussed.
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Stanga, Serena, Anna Caretto, Marina Boido, and Alessandro Vercelli. "Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases." International Journal of Molecular Sciences 21, no. 10 (May 25, 2020): 3719. http://dx.doi.org/10.3390/ijms21103719.
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Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the “mitochondrial switch” which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.
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McMillan, H. J., B. Gerber, T. Cowling, W. Khuu, M. Mayer, J. W. Wu, B. Maturi, K. Klein-Panneton, C. Cabalteja, and H. Lochmüller. "Burden of Spinal Muscular Atrophy (SMA) on Patients and Caregivers in Canada." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 553–68. http://dx.doi.org/10.3233/jnd-200610.
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Background: Spinal muscular atrophy (SMA) is a rare neurodegenerative disease characterized by progressive muscular weakness, which occurs in one in 6,000 to 10,000 live births. The burden of SMA on Canadian patients and caregivers is not known. Objective: To characterize the burden of SMA in Canada as reported by patients and caregivers, including disease and treatment impacts, indirect costs, and caregiver burden. Methods: Surveys were distributed by Cure SMA Canada and Muscular Dystrophy Canada to individuals with SMA and their caregivers. The online surveys were anonymous and completed between January 28 and February 21, 2020. Results: 965 patient and 962 caregiver responses met the eligibility criteria. Patients reported SMA subtypes as: type I (25.0%), type II (41.3%), type III (29.3%). Using the EQ-5D, patients were shown to have impaired quality of life with an average health utility index of 0.49 (SD: 0.26). The median expenditure was $4,500 CAD (IQR: $1,587 – $11,000) for assistive devices; $6,800 CAD (IQR: $3,900–$13,000) on health professional services; and $1,200 CAD (IQR: $600 –$3,100) on SMA-related travel and accommodation in the past 12 months. Caregivers reported needing respite care (45.7%), physiotherapy for an injury from a lift/transfer (45.7%), or other health impacts (63.3%). Caregivers reported changes to personal plans, sleep disturbances, and work adjustments, with a mean Caregiver Strain Index score of 7.5 [SD: 3.3]. Conclusion: SMA in Canada is associated with a significant burden for patients and their caregivers.
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Chen, Tai-Heng. "Circulating microRNAs as potential biomarkers and therapeutic targets in spinal muscular atrophy." Therapeutic Advances in Neurological Disorders 13 (January 2020): 175628642097995. http://dx.doi.org/10.1177/1756286420979954.
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Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of particular groups of motor neurons (MNs) in the anterior horn of the spinal cord with progressive muscle wasting. SMA is caused by a deficiency of the survival motor neuron (SMN) protein due to a homozygous deletion or mutation of the SMN1 gene. However, the molecular mechanisms whereby the SMN complex regulates MN functions are not fully elucidated. Emerging studies on SMA pathogenesis have turned the attention of researchers to RNA metabolism, given that increasingly identified SMN-associated modifiers are involved in both coding and non-coding RNA (ncRNA) processing. Among various ncRNAs, microRNAs (miRNAs) are the most studied in terms of regulation of posttranscriptional gene expression. Recently, the discovery that miRNAs are critical to MN function and survival led to the study of dysregulated miRNAs in SMA pathogenesis. Circulating miRNAs have drawn attention as a readily available biomarker due to their property of being clinically detectable in numerous human biofluids through non-invasive approaches. As there are recent promising findings from novel miRNA-based medicines, this article presents an extensive review of the most up-to-date studies connecting specific miRNAs to SMA pathogenesis and the potential applications of miRNAs as biomarkers and therapeutic targets for SMA.
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McEwan, I. J. "Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy." Biochemical Society Transactions 29, no. 2 (May 1, 2001): 222–27. http://dx.doi.org/10.1042/bst0290222.
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The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.
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Paul, Sujay, Luis Alberto Bravo Vázquez, Samantha Pérez Uribe, Paula Roxana Reyes-Pérez, and Ashutosh Sharma. "Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders." Cells 9, no. 7 (July 15, 2020): 1698. http://dx.doi.org/10.3390/cells9071698.
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MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, we provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, Friedreich’s Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. We also discuss the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.
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Sleeman, Judith. "Small nuclear RNAs and mRNAs: linking RNA processing and transport to spinal muscular atrophy." Biochemical Society Transactions 41, no. 4 (July 18, 2013): 871–75. http://dx.doi.org/10.1042/bst20120016.
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The splicing of pre-mRNA by the spliceosome is a characteristic feature of eukaryotic cells, dependent on a group of snRNPs (small nuclear ribonucleoproteins). These splicing snRNPs have a complex assembly pathway involving multiple steps that take place in different regions of the cell, which is reflected in their complex subcellular distribution. Vital to the assembly of splicing snRNPs is the protein SMN (survival of motor neurons). In multicellular organisms, SMN acts in the cytoplasm, together with its associated protein complex to assemble a heptameric ring of proteins called the Sm proteins as an early stage in splicing snRNP assembly. A deficiency of the SMN protein results in the inherited neurodegenerative condition SMA (spinal muscular atrophy), a leading cause of infant mortality specifically affecting spinal motor neurons. It has long been a puzzle how lowered levels of a protein required for a process as fundamental as splicing snRNP assembly can result in a condition with such a definite cell-type-specificity. The present review highlights recent research that points to wider roles in RNA metabolism for both SMN itself and the Sm proteins with which it is linked.
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Dobrowolski, Steven F., Ha T. Pham, Frances Pouch Downes, Thomas W. Prior, Edwin W. Naylor, and Kathy J. Swoboda. "Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling." Clinical Chemistry 58, no. 6 (June 1, 2012): 1033–39. http://dx.doi.org/10.1373/clinchem.2012.183038.
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Abstract BACKGROUND The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%–98% of affected patients. METHODS We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn screening tests. RESULTS Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive. CONCLUSIONS This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA-affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening.
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Ikeda, Toshio, Akihiko Nakahara, Rie Nagano, Maiko Utoyama, Megumi Obara, Hiroshi Moritake, Tamayo Uechi, et al. "TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy." Journal of Human Genetics 62, no. 4 (December 8, 2016): 473–80. http://dx.doi.org/10.1038/jhg.2016.149.
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Hassan, Zurina, and Raghava N. Sriramaneni. "Insights of the pathophysiology of neurodegenerative diseases and the role of phytochemical compounds in its management." Neuroscience Research Notes 4, no. 3 (August 28, 2021): 1–10. http://dx.doi.org/10.31117/neuroscirn.v4i3.77.
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A neurodegenerative disease (ND) is defined as an irreversible disorder in most cases, leading to progressive loss of neurons and intellectual abilities. ND can lead to fatality in most circumstances, and the elderly above the age of sixty-five (65) constitute the major risk category. The most common type of ND includes Alzheimer's disease (AD), and Parkinson's disease (PD). Other NDs are Huntington's disease (HD), motor neuron disease (MND), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), and prion disease. ND strikes mainly in the middle to late life incidence expected to rise as the population ages.
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Remtulla, S., E. Zapata-Aldana, H. Gonorazky, J. Boyd, C. Scholtes, R. Hicks, A. Leung, et al. "B.07 Review of patients with Spinal Muscular Atrophy treated with Nusinersen in Ontario." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S13. http://dx.doi.org/10.1017/cjn.2018.95.
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Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.
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Blatnik, Anton J., Vicki L. McGovern, and Arthur H. M. Burghes. "What Genetics Has Told Us and How It Can Inform Future Experiments for Spinal Muscular Atrophy, a Perspective." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8494. http://dx.doi.org/10.3390/ijms22168494.
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Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by motor neuron loss and subsequent atrophy of skeletal muscle. SMA is caused by deficiency of the essential survival motor neuron (SMN) protein, canonically responsible for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). Therapeutics aimed at increasing SMN protein levels are efficacious in treating SMA. However, it remains unknown how deficiency of SMN results in motor neuron loss, resulting in many reported cellular functions of SMN and pathways affected in SMA. Herein is a perspective detailing what genetics and biochemistry have told us about SMA and SMN, from identifying the SMA determinant region of the genome, to the development of therapeutics. Furthermore, we will discuss how genetics and biochemistry have been used to understand SMN function and how we can determine which of these are critical to SMA moving forward.
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Jiang, Xiaoting, Annapoorna Kannan, and Laxman Gangwani. "ZPR1-Dependent Neurodegeneration Is Mediated by the JNK Signaling Pathway." Journal of Experimental Neuroscience 13 (January 2019): 117906951986791. http://dx.doi.org/10.1177/1179069519867915.
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The zinc finger protein ZPR1 deficiency causes neurodegeneration and results in a mild spinal muscular atrophy (SMA)-like disease in mice with reduced Zpr1 gene dosage. Mutation of the survival motor neuron 1 ( SMN1) gene causes SMA. Spinal muscular atrophy is characterized by the degeneration of the spinal cord motor neurons caused by chronic low levels of SMN protein. ZPR1 interacts with SMN and is required for nuclear accumulation of SMN. Patients with SMA express reduced levels of ZPR1. Reduced Zpr1 gene dosage increases neurodegeneration and severity of SMA disease in mice. Mechanisms underlying ZPR1-dependent neurodegeneration are largely unknown. We report that neurodegeneration caused by ZPR1 deficiency is mediated by the c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPK). ZPR1-dependent neuron degeneration is mediated by central nervous system (CNS)-specific isoform JNK3. ZPR1 deficiency activates the MAPK signaling cascade, MLK3 → MKK7 → JNK3, which phosphorylates c-Jun and activates caspase-mediated neuron degeneration. Neurons from Jnk3-null mice show resistance to ZPR1-dependent neurodegeneration. Pharmacologic inhibition of JNK reduces degeneration of ZPR1-deficient neurons. These data show that ZPR1-dependent neurodegeneration is mediated by the JNK signaling pathway and suggest that ZPR1 downregulation in SMA may contribute to JNK-mediated neurodegeneration associated with SMA pathogenesis.
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Malacarne, Claudia, Mariarita Galbiati, Eleonora Giagnorio, Paola Cavalcante, Franco Salerno, Francesca Andreetta, Cinza Cagnoli, et al. "Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients." International Journal of Molecular Sciences 22, no. 11 (May 26, 2021): 5673. http://dx.doi.org/10.3390/ijms22115673.
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Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.
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Elorza, Ainara, Yamile Márquez, Jorge R. Cabrera, José Luis Sánchez-Trincado, María Santos-Galindo, Ivó H. Hernández, Sara Picó, et al. "Huntington’s disease-specific mis-splicing unveils key effector genes and altered splicing factors." Brain 144, no. 7 (March 16, 2021): 2009–23. http://dx.doi.org/10.1093/brain/awab087.
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Abstract Correction of mis-splicing events is a growing therapeutic approach for neurological diseases such as spinal muscular atrophy or neuronal ceroid lipofuscinosis 7, which are caused by splicing-affecting mutations. Mis-spliced effector genes that do not harbour mutations are also good candidate therapeutic targets in diseases with more complex aetiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue to identify such key pathogenic mis-spliced genes. Nevertheless, while analysis of tumour or dystrophic muscle biopsies can be informative on early stage pathogenic mis-splicing, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington’s disease pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the Huntington’s disease-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked mis-spliced effector genes that—together with the deregulated splicing factors—become new possible therapeutic targets. In summary, here we report pathogenic global mis-splicing in Huntington’s disease striatum captured by our new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.
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Mendonça, Rodrigo de Holanda, Hermann dos Santos Fernandes, Rafael Barbéro Schimmelpfeng Pinto, Ciro Matsui Júnior, Graziela Jorge Polido, André Macedo Serafim da Silva, Luis Fernando Grossklauss, Umbertina Conti Reed, and Edmar Zanoteli. "Managing intrathecal administration of nusinersen in adolescents and adults with 5q-spinal muscular atrophy and previous spinal surgery." Arquivos de Neuro-Psiquiatria 79, no. 2 (February 2021): 127–32. http://dx.doi.org/10.1590/0004-282x-anp-2020-0200.
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ABSTRACT Background: Spinal muscular atrophy (SMA) is a neurodegenerative disease of lower motor neurons associated with frequent occurrence of spinal deformity. Nusinersen is an antisense oligonucleotide that increases SMN protein level and is administrated by frequent intrathecal lumbar injections. Thus, spinal deformities and previous spinal surgery are important challenges for drug delivery in SMA. Objective: To report imaging methods used for Nusinersen injection in SMA patients. Methods: Nusinersen injection procedures in SMA types 2 and 3 patients who had previous spinal surgery were analyzed retrospectively to describe the imaging and puncture procedures, as well as the occurrence of complications. Results: Nine SMA patients (14 to 50 years old) underwent 57 lumbar punctures for nusinersen injection. Six patients had no interlaminar space available; in five of them, a transforaminal approach was used, and another one underwent a surgery to open a posterior bone window for the injections. Transforaminal puncture was performed using CT scan in three cases and fluoroscopy in the other two, with a similar success rate. One patient in the transforaminal group had post-procedure radiculitis, and another one had vagal reaction (hypotension). In three cases, with preserved interlaminar space, injections were performed by posterior interlaminar puncture, and only one adverse event was reported (post-puncture headache). Conclusion: In SMA patients with previous spinal surgery, the use of imaging-guided intervention is necessary for administering intrathecal nusinersen. Transforaminal technique is indicated in patients for whom the interlaminar space is not available, and injections should always be guided by either CT or fluoroscopy.
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Pyatt, Robert E., David C. Mihal, and Thomas W. Prior. "Assessment of Liquid Microbead Arrays for the Screening of Newborns for Spinal Muscular Atrophy." Clinical Chemistry 53, no. 11 (November 1, 2007): 1879–85. http://dx.doi.org/10.1373/clinchem.2007.092312.
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Abstract Background: Spinal muscular atrophy is a common neurodegenerative disorder that has recently been considered for inclusion in the next generation of newborn screening regimens. We sought to validate liquid microbead arrays for the identification of affected individuals by direct DNA analysis. Methods: Assays were created to detect the homozygous deletions in exon 7 of the SMN1 gene found in approximately 95% of affected individuals by use of 2 different microbead chemistries on the Luminex 200: MultiCode-PLx and Tag-It. A series of 367 blood spots including 164 from affected individuals, 46 from known carriers, and 157 from unaffected individuals were then analyzed with each assay. Results: The MultiCode-PLx assay required 4.2 h to perform and provided correct identification of all 164 samples from affected individuals. Correct exclusion was also made for all 46 carrier and 157 unaffected individual samples. The Tag-It assay required 6.8 h, detected all samples from affected individuals, and excluded all but 1 (99.5%) of the samples from carriers and unaffected individuals. Neither method was sensitive to increasing copy numbers of the SMN2 gene. Conclusions: Both methods showed high sensitivity and specificity for the detection of patients with spinal muscular atrophy. For both methods, ample DNA was extracted from all blood spots for analysis, and SMN2 copy numbers did not interfere. Liquid bead arrays represent a robust method for DNA analysis in newborn screening laboratories.
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Huang, Shanshan, Suiqiang Zhu, Xiao-Jiang Li, and Shihua Li. "The Expanding Clinical Universe of Polyglutamine Disease." Neuroscientist 25, no. 5 (January 7, 2019): 512–20. http://dx.doi.org/10.1177/1073858418822993.
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Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of unstable polyQ repeats in their associated disease proteins. To date, the pathogenesis of each disease remains poorly understood, and there are no effective treatments. Growing evidence has indicated that, in addition to neurodegeneration, polyQ-expanded proteins can cause a wide array of abnormalities in peripheral tissues. Indeed, polyQ-expanded proteins are ubiquitously expressed throughout the body and can affect the function of both the central nervous system (CNS) and peripheral tissues. The peripheral effects of polyQ disease proteins include muscle wasting and reduced muscle strength in patients or animal models of spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia type 17 (SCA17). Since skeletal muscle pathology can reflect disease progression and is more accessible for treatment than neurodegeneration in the CNS, understanding how polyQ disease proteins affect skeletal muscle will help elucidate disease mechanisms and the development of new therapeutics. In this review, we focus on important findings in terms of skeletal muscle pathology in polyQ diseases and also discuss the potential mechanisms underlying the major peripheral effects of polyQ disease proteins, as well as their therapeutic implications.
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Hensel, Niko, Hermann Brickwedde, Konstantinos Tsaknakis, Antonia Grages, Lena Braunschweig, Katja A. Lüders, Heiko M. Lorenz, et al. "Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy." Human Molecular Genetics 29, no. 16 (July 9, 2020): 2662–73. http://dx.doi.org/10.1093/hmg/ddaa145.
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Abstract Spinal muscular atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the survival of motoneuron gene 1 resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development is a key feature of SMA, but it is yet unknown whether this is an indirect functional consequence of muscle weakness or caused by bone-intrinsic mechanisms. Therefore, we radiologically examined SMA patients in a prospective, non-randomized cohort study characterizing bone size and bone mineral density (BMD) and performed equivalent measurements in pre-symptomatic SMA mice. BMD as well as lumbar vertebral body size were significantly reduced in SMA patients. This growth defect but not BMD reduction was confirmed in SMA mice by μCT before the onset of neuromuscular symptoms indicating that it is at least partially independent of neuromuscular degeneration. Interestingly, the number of chondroblasts in the hypertrophic zone of the growth plate was significantly reduced. This was underlined by RNAseq and expression data from developing SMA mice vertebral bodies, which revealed molecular changes related to cell division and cartilage remodeling. Together, these findings suggest a bone intrinsic defect in SMA. This phenotype may not be rescued by novel drugs that enhance SMN levels in the central nervous system only.
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Renier, Kayla J., Sandra M. Troxell-Smith, Jamie A. Johansen, Masahisa Katsuno, Hiroaki Adachi, Gen Sobue, Jason P. Chua, et al. "Antiandrogen Flutamide Protects Male Mice From Androgen-Dependent Toxicity in Three Models of Spinal Bulbar Muscular Atrophy." Endocrinology 155, no. 7 (July 1, 2014): 2624–34. http://dx.doi.org/10.1210/en.2013-1756.
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Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.
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Perez, Barbara A., Alison Shutterly, Ying Kai Chan, Barry J. Byrne, and Manuela Corti. "Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases." Brain Sciences 10, no. 2 (February 22, 2020): 119. http://dx.doi.org/10.3390/brainsci10020119.
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Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.
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Farrar, Michelle, Kathryn J. Swoboda, Meredith Schultz, Hugh McMillan, Julie Parsons, Ian E. Alexander, Elaine Kernbauer, et al. "014 AVXS-101 gene-replacement therapy (GRT) in presymptomatic spinal muscular atrophy (SMA): study update." Journal of Neurology, Neurosurgery & Psychiatry 90, e7 (July 2019): A5.3—A6. http://dx.doi.org/10.1136/jnnp-2019-anzan.14.
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IntroductionSMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns.MethodsSPR1NT is a multicenter, open-label, phase 3 study (NCT03505099) enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1×1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]).ResultsFrom April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). As of January 31, 2019, 15 asymptomatic infants have been enrolled in SPR1NT and dosed with AVXS-101. Updated data available at the time of the congress will be presented.ConclusionsPreliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.
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Schultz, M., K. Swoboda, M. Farrar, H. McMillan, J. Parsons, M. Farrow, FG Ogrinc, et al. "P.065 AVXS-101 gene-replacement therapy (GRT)) in presymptomatic spinal muscular atrophy (SMA): study update." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, s1 (June 2019): S31—S32. http://dx.doi.org/10.1017/cjn.2019.165.
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Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of SMN1. Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns. Methods: SPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1x1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]). Results: From April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline CHOP-INTEND score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). Updated data available at the time of the congress will be presented. Conclusions: Preliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.
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Woo, Caroline J., Verena K. Maier, Roshni Davey, James Brennan, Guangde Li, John Brothers, Brian Schwartz, et al. "Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy." Proceedings of the National Academy of Sciences 114, no. 8 (February 13, 2017): E1509—E1518. http://dx.doi.org/10.1073/pnas.1616521114.
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Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations inSMN1(Survival Motor Neuron 1). The disease severity inversely correlates with the copy number ofSMN2,a duplicated gene that is nearly identical toSMN1.We have delineated a mechanism of transcriptional regulation in theSMN2locus. A previously uncharacterized long noncoding RNA (lncRNA),SMN-antisense 1(SMN-AS1), repressesSMN2expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction betweenSMN-AS1and PRC2 inhibit the recruitment of PRC2 and increaseSMN2expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci.
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Duff, J., P. Davies, K. Watt, and I. J. McEwan. "Structural dynamics of the human androgen receptor: implications for prostate cancer and neurodegenerative disease." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1098–102. http://dx.doi.org/10.1042/bst0341098.
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The AR (androgen receptor) is a ligand-activated transcription factor that mediates the action of the steroids testosterone and dihydrotestosterone. Alterations in the AR gene result in a number of clinical disorders, including: androgen-insensitivity, which leads to disruption of male development; prostate cancer; and a neuromuscular degenerative condition termed spinal bulbar muscular atrophy or Kennedy's disease. The AR gene is X-linked and the protein is coded for by eight exons, giving rise to a C-terminal LBD (ligand-binding domain; exons 4–8), linked by a hinge region (exon 4) to a Zn-finger DBD (DNA-binding domain; exons 2 and 3) and a large structurally distinct NTD (N-terminal domain; exon 1). Identification and characterization of mutations found in prostate cancer and Kennedy's disease patients have revealed the importance of structural dynamics in the mechanisms of action of receptors. Recent results from our laboratory studying genetic changes in the LBD and the structurally flexible NTD will be discussed.
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Kannan, Annapoorna, Xiaoting Jiang, Lan He, Saif Ahmad, and Laxman Gangwani. "ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy." Brain 143, no. 1 (December 12, 2019): 69–93. http://dx.doi.org/10.1093/brain/awz373.
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Abstract Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene. A second copy, SMN2, is similar to SMN1 but produces ∼10% SMN protein because of a single-point mutation that causes splicing defects. Chronic low levels of SMN cause accumulation of co-transcriptional R-loops and DNA damage leading to genomic instability and neurodegeneration in SMA. Severity of SMA disease correlates inversely with SMN levels. SMN2 is a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SMN genes are largely unknown. We report that zinc finger protein ZPR1 binds to RNA polymerase II, interacts in vivo with SMN locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and influences SMN2 expression levels in SMA patient cells. ZPR1 overexpression in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice. ZPR1-dependent rescue improves growth and motor function and increases the lifespan of male and female SMA mice. ZPR1 reduces neurodegeneration in SMA mice and prevents degeneration of cultured primary spinal cord neurons derived from SMA mice. Further, we show that the low levels of ZPR1 associated with SMA pathogenesis cause accumulation of co-transcriptional RNA-DNA hybrids (R-loops) and DNA damage leading to genomic instability in SMA mice and patient cells. Complementation with ZPR1 elevates senataxin levels, reduces R-loop accumulation and rescues DNA damage in SMA mice, motor neurons and patient cells. In conclusion, ZPR1 is critical for preventing accumulation of co-transcriptional R-loops and DNA damage to avert genomic instability and neurodegeneration in SMA. ZPR1 enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPR1 represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA.
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Patani, Rickie. "Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells." Stem Cells International 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/1036974.
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Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevantin vitrodisease models. I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability usingin vitrohuman disease models.
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de Tommaso, Marina, Lars Arendt-Nielsen, Ruth Defrin, Miriam Kunz, Gisele Pickering, and Massimiliano Valeriani. "Pain in Neurodegenerative Disease: Current Knowledge and Future Perspectives." Behavioural Neurology 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/7576292.
Full textAbstract:
Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington’s disease (HD), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA), is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed.
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Vegeto, Elisabetta, Alessandro Villa, Sara Della Torre, Valeria Crippa, Paola Rusmini, Riccardo Cristofani, Mariarita Galbiati, Adriana Maggi, and Angelo Poletti. "The Role of Sex and Sex Hormones in Neurodegenerative Diseases." Endocrine Reviews 41, no. 2 (September 23, 2019): 273–319. http://dx.doi.org/10.1210/endrev/bnz005.
Full textAbstract:
Abstract Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type—either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer’s disease, Parkinson’s diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.