Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Abstract

Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

Removal of the Polyglutamine Repeat of Ataxin-3 by Redirecting pre-mRNA Processing

“…However, this would need to be the subject of functional studies to determine the effect of removing regions of other polyQ proteins. For example, Huntington’s disease is unlikely to be amenable to exon skipping, as the polyQ tract is located in the initial exon [3]. Here, we show removal of ATXN3 exon 10, and consequently the polyQ repeat from the normal and expanded ataxin-3 protein, using two different AO chemistries.…”

“…We show significant knockdown of the full-length ataxin-3 isoforms encoded by both alleles, as well as modification of the ataxin-3 protein to produce a truncated protein, missing the polyQ tract. While the impact of global ataxin-3 knockdown is under debate [8,47,48], the role of ataxin-3 in the ubiquitin-proteasome machinery is well-established, and there are conflicting views as to whether ataxin-3 is essential in maintaining normal cellular function [3,49,50]. Figiel and colleagues (2011) created a functional Atxn3 knockout mouse that showed no obvious phenotype, with a life span comparable to that of the wildtype mouse [48].…”

“…Spinocerebellar ataxia type 3 (SCA3) is a progressive, typically late-onset autosomal dominant neurodegenerative disease [1]. SCA3 is one of a larger group of diseases, termed, the polyglutamine (polyQ) diseases [2,3]. These diseases all share a common pathogenic mechanism; an expanded CAG repeat in the coding sequence of nine genes, and in the case of SCA3, the CAG expansion is located in the penultimate exon (exon 10) of ATXN3 (14q32.1) [4].…”

“…The expanded CAG repeat located in exon 10 of ATXN3 results in the addition of an extended glutamine tract in ataxin-3, directly leading to conformational changes that give the protein a toxic gain of function(s), as well as subjecting the protein to formation of neuronal nuclear inclusions [7]. Although SCA3 is clinically heterogeneous in presentation, the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected individual [3]. Despite arising from a single variant gene, the pathogenesis of SCA3 has been difficult to characterize, as several toxic pathways and mechanisms have been proposed to play a role in the disease.…”

Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review

“…In SCA, abnormal expansion of CAG repeats in respective coding regions of SCA leads to elongated translation of the polyglutamine (polyQ) tract. When the expansion reaches a specific threshold, it causes the abnormal configuration of the encoded polyQ protein, leading to protein aggregation and nuclear inclusions, a pathological hallmark of SCA [ 67 ]. The presence of polyQ aggregates are detrimental to cellular processes, and contributes to cellular dysfunction and death [ 68 , 69 ].…”