PERSPECTIVE Ataxin-3, DNA Damage Repair, and SCA3 Cerebellar Degeneration: On the Path to Parsimony?

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder, characterized by progressive ataxia, spasticity, and ocular movement abnormalities. The SCA3 gene, ATXN3, was identified in 1994 and contains a CAG repeat tract that increases from 12–41 to 62–84 in the disease state to produce ataxin-3 protein containing a polyglutamine (polyQ) expansion [1]. SCA3 is the most common inher-ited ataxia, yet a thorough understanding of the molecular basis of this disease has remained elusive. Initial studies found that ataxin-3 interacts with two proteins, HHR23A and HHR23B, that are both homologs of the DNA repair protein Rad23 [2]. Further work revealed ataxin-3 as a bona fide deubiquitinating enzyme [3,4], thereby providing a crucial insight into ataxin-3’s normal function. More recently, ataxin-3 was shown to interact with the transcription factor FOXO4 as a transcriptional coactivator in the oxidative stress response [5]. Thus, while some very basic functions of ataxin-3 have been established, these advances have yielded noninter-secting lines of investigation and have not provided an underlying mechanism for SCA3 disease pathogenesis. In this issue of PLOS Genetics, two complementary papers establish a key function o