Mutant Ataxin-3-Containing Aggregates (MATAGGs) in Spinocerebellar Ataxia Type 3: Dynamics of the Disorder

Abstract

Spinocerebellar ataxia type 3 (SCA3) is the most common type of SCA worldwide caused by abnormal polyglutamine expansion in the coding region of the ataxin-3 gene. Ataxin-3 is a multi-faceted protein involved in various cellular processes such as deubiquitination, cytoskeletal organisation, and transcriptional regulation. The presence of an expanded poly(Q) stretch leads to altered processing and misfolding of the protein culminating in the production of insoluble protein aggregates in the cell. Various post-translational modifications affect ataxin-3 fibrillation and aggregation. This review provides an exhaustive assessment of the various pathogenic mechanisms undertaken by the mutant ataxin-3-containing aggregates (MATAGGs) for disease induction and neurodegeneration. This includes in-depth discussion on MATAGG dynamics including their formation, role in neuronal pathogenesis, and the debate over the toxic v/s protective nature of the MATAGGs in disease progression. Additionally, the currently available therapeutic strategies against SCA3 have been reviewed. The shift in the focus of such strategies, from targeting the steps that lead to or reduce aggregate formation to targeting the expression of mutant ataxin-3 itself via RNA-based therapeutics, has also been presented. We also discuss the intriguing promise that various growth and neurotrophic factors, especially the insulin pathway, hold in the modulation of SCA3 progression. These emerging areas show the newer directions through which SCA3 can be targeted including various preclinical and clinical trials. All these advances made in the last three decades since the discovery of the ataxin-3 gene have been critically reviewed here.

Keywords: Ataxin-3; CAG repeat; Deubiquitinase; Insulin; MATAGGs; MATIBs; MJD1; Machado-Joseph disease; Nuclear inclusion bodies; Poly(Q) aggregates; Polyglutamine toxicity; Spinocerebellar ataxia.