Ataxin-2: From RNA Control to Human Health and Disease

Abstract

RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases.

Keywords: ALS; RNA metabolism; RNA-DNA hybrids; SCA2; stress granules.

Figure 1

Structure of Ataxin-2 and its conserved domains across model species. The RNA-binding domains of Ataxin-2, Like-Sm (LSm) and LSm-associated (LSmAD), are located at the N-terminal region and are conserved across species. The C-terminal region of Ataxin-2 harbours a PAM2 domain, which interacts with the poly(A)-binding protein (PABP1). A polyglutamine (polyQ) tract is also located in the N-terminal of most mammalian species. For species with multiple Q residues upstream of the LSm/LSmAD domains (S. pombe, D. rerio, M. musculus), the Q represented was chosen based on amino acid sequence similarities with the regions flanking the polyQ site in human ATXN2. Conserved proline-rich domains are also depicted (consensus sequences: PPAXPTXXSP and PPSRPSRPPS). ATSS = alternative translational start site.

Figure 2

Functions of Ataxin-2 proteins under stressed and non-stressed conditions. Studies from a variety of model organisms demonstrate a role for Ataxin-2 proteins in the regulation of mRNA polyadentylation, stability, translation, R-loops, circadian rhythms, branched-chain amino acid (BCAA) metabolism, mTOR activity, stress granule (SG) assembly, and P-body morphology. Dashed lines represent indirect regulation by Ataxin-2. Reference numbers for papers are shown.

Figure 3

Multifaceted functions of Ataxin-2 and links to disease. Ataxin-2 functions to regulate several stages of RNA processing, with roles in physiological pathways. These functions include promoting mRNA stability and translation, as well as the regulation of R-loop and stress granule formation. These functions contribute to the control of metabolic pathways such as TOR and circadian rhythmicity. Deregulation of any of these processes can give rise to a wide range of cellular dysfunction, which can promote disease. SCA2, spinocerebellar ataxia type II; ALS, amyotrophic lateral sclerosis; PD, Parkinson’s disease; SCA1, spinocerebellar ataxia type I; MJD, Machado-Joseph’s disease; POAG, primary open angle glaucoma.