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.
Highlights
Spinocerebellar ataxia type 3 (SCA3) or Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder which is one of the polyglutamine disorders
Mutated ATXN3 alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3
We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients
Summary
Spinocerebellar ataxia type 3 (SCA3) or Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder which is one of the polyglutamine (polyQ) disorders. It is caused by expansion of a CAG triplet in the coding region of a gene. The CAG repeat is translated into an extended glutamine stretch in the mutant protein, resulting gain of toxic function, which induces neuronal loss in various regions of the brain [1]. In this review, according to current knowledge of normal and mutant polyQ expanded ataxin-3 functions, as well as the toxic mechanisms of mutant ataxin-3 RNA and protein and potential therapeutic strategies will be discussed, which may improve the sign, symptoms and slow the disease progression of SCA3
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