Toward understanding Machado-Joseph disease

Abstract

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

Figure 1

Functional domains and posttranslational modifications of ATXN3. A) ATXN3 contains a N-terminal DUB catalytic domain (Josephin domain, JD) centered on residues Q9, C14, H119, and N134 (red), two Ub-binding sites, and two nuclear export signals (NES77 and NES141). The C-terminal region of ATXN3 contains 2 or 3 UIMs (depending on the isoform), the polyQ tract (Qn), and the NLS. ATXN3 is mono-ubiquitinated primarily at residue K117 and phosphorylated at residues S111, S236, S256, S340, and S352. B) Solution structure of JD (PDB: 1YZB) highlighting the catalytic residues (red) and critical residues of Ub-binding sites (blue). Ub-binding site 1 (I77Q78) resides near the catalytic pocket while Ub-binding site 2 (W87) resides on the opposite side, separated from site 1 by a helical hairpin (hh). The main ATXN3 mono-ubiquitination site, K117 (green), also localizes near the catalytic cleft.