Pathogenesis of SCA3 and implications for other polyglutamine diseases

Abstract

Tandem repeat diseases include the neurodegenerative disorders known as polyglutamine (polyQ) diseases, caused by CAG repeat expansions in the coding regions of the respective disease genes. The nine known polyQ disease include Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and six spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17). The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate. Among the polyQ diseases, SCA3 is the most common SCA, and second to HD in prevalence worldwide. Here we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.

Keywords: ATXN3; Ataxin-3; Deubiquitinase; MJD; Machado Joseph disease; Neurodegenerative disease; Polyglutamine disease; SCA3; Spinocerebellar Ataxia.

Figure 1.. Schematic of ATXN3 protein.

The N-terminal Josephin domain contains the deubiquitinase (DUB) catalytic site (C14), as well as nuclear export sites (NES) and a small ubiquitin-like modifier [SUMO]-interacting motif (SIM). The C-terminal tail contains two or three ubiquitin-interacting motifs (UIMs), a putative nuclear localization signal (NLS) and the variable polyQ repeat. Repeat lengths of normal and pathogenic polyQ are shown. ATXN3 can be post-translationally modified by ubiquitin (Ub) at K117, sumoylation (S) at K166 and K356, and phosphorylation at S12, S236, S256, S260, S261, S335, and S347.

Figure 2.. Components of the Ubiquitin Signaling System.

Ubiquitin conjugation to proteins serves diverse roles beyond the ubiquitin proteasome system (UPS), including roles in DNA repair, autophagy, subcellular localization and trafficking, and alterations in protein interactions. As a DUB, ATXN3 has been most closely associated with the UPS but increasingly is linked to other ubiquitin-dependent pathways shown here. Accordingly, in studies of SCA3 and other polyQ diseases, more attention should be paid to broader impairments in the ubiquitin signaling system beyond the UPS. Perturbations in ubiquitin homeostasis in one arm (e.g. the UPS) could have important, indirect effects on other arms of the ubiquitin signaling system (USS).

Figure 3.. Normal and pathogenic roles of ATXN3 in the DNA damage response (DDR).

The DDR is a series of complex interconnected pathways that function to detect, signal, and repair DNA damage. DDR is initiated by phosphorylation of ATM or ATR apical kinases. Activated ATM/ATR phosphorylate mediator proteins (i.e. MDC1) that remodel damaged chromatin leading to recruitment of DNA repair factors (i.e. PNKP) that process and repair DNA. Cell cycle regulators (i.e. Chk1 and p53) are also activated by ATM/ATR to stall cell cycle progression during DNA repair. (Left) Normal ATXN3 regulates the kinetics of early and late events in the DDR process. As a deubiquitinase, ATXN3 stabilizes MDC1, Chk1, and p53 through the removal of poly -ubiquitin chains, and promotes PNKP phosphatase activity through an unclear mechanism, to promote DNA repair and cell survival. (Right) Conversely, poly glutamine-expanded mutant ATXN3 (mutATXN3) inhibits PNKP-dependent DNA repair and prolongs p53-signaling through enhanced p53-binding and stabilization. Unrepaired DNA damage and/or sustained p53-activation by mutATXN3 leads to increased activation of pro-apoptotic pathways and cell vulnerability to DNA damage. (MDC1=mediator of DNA damage checkpoint protein 1; Chk1=checkpoint protein 1; p53=tumor protein 53; PNKP=poly nucleotide kinase-phosphatase; ATM=ataxia telangiectasia mutated; ATR=ataxia telangiectasia and Rad3-related protein).