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Gardian, G., Browne, S.E., Choi, D.K., Klivenyi, P., Gregorio, J., Kubilus, J.K., Ryu, H., Langley, B., Ratan, R.R., Ferrante, R.J. and Beal, M.F. (2005) Neuroprotective Effects of Phenylbutyrate in the N171-82Q Transgenic Mouse Model of Huntington’s Disease. The Journal of Biological Chemistry, 280, 556-563.
https://doi.org/10.1074/jbc.M410210200

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• TITLE: Emerging Concepts of Pathogenesis and Comprehensive Therapeutic Strategies for Spinocerebellar Ataxia Type 3

  AUTHORS: Sagor Kumar Roy, Xiaolei Liu

  KEYWORDS: Spinocerebellar Ataxia Type 3, Machado-Joseph Disease, Polyglutamine Disease, Ataxin-3, Therapeutic Strategies

  JOURNAL NAME: Neuroscience and Medicine, Vol.12 No.1, March 19, 2021

  ABSTRACT: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the ATXN3 gene, situated at 14q32.1. The ATXN3 gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated ATXN3 alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues); the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.