Ataxin‐2: A versatile posttranscriptional regulator and its implication in neural function

Abstract

Ataxin-2 (ATXN2) is a eukaryotic RNA-binding protein that is conserved from yeast to human. Genetic expansion of a poly-glutamine tract in human ATXN2 has been implicated in several neurodegenerative diseases, likely acting through gain-of-function effects. Emerging evidence, however, suggests that ATXN2 plays more direct roles in neural function via specific molecular and cellular pathways. ATXN2 and its associated protein complex control distinct steps in posttranscriptional gene expression, including poly-A tailing, RNA stabilization, microRNA-dependent gene silencing, and translational activation. Specific RNA substrates have been identified for the functions of ATXN2 in aspects of neural physiology, such as circadian rhythms and olfactory habituation. Genetic models of ATXN2 loss-of-function have further revealed its significance in stress-induced cytoplasmic granules, mechanistic target of rapamycin signaling, and cellular metabolism, all of which are crucial for neural homeostasis. Accordingly, we propose that molecular evolution has been selecting the ATXN2 protein complex as an important trans-acting module for the posttranscriptional control of diverse neural functions. This explains how ATXN2 intimately interacts with various neurodegenerative disease genes, and suggests that loss-of-function effects of ATXN2 could be therapeutic targets for ATXN2-related neurological disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

The Disease-Associated ProteinsDrosophilaNab2 and Ataxin-2 Interact with Shared RNAs and Coregulate Neuronal Morphology

“…If Drosophila Nab2 also performs some or all of these nuclear processing roles on its associated RNAs, then Nab2 binding should contribute to transcript stability, nuclear export, and ultimately protein expression. Atx2, in contrast, is a key regulator of translational efficiency in the cytoplasm, suppressing the translation of some target RNAs and activating the translation of others (reviewed in Lee et al 2018). As our data suggest Nab2 and Atx2 act in functional opposition on a shared transcript set, we propose Atx2 primarily functions as a translational inhibitor rather than activator on shared Nab2-and Atx2-associated RNAs.…”

Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons

“…Here we focus on the strongest modifier of HttQ128 from this screen, Ataxin2 ( Atx2; S1 Fig). Atx2 is an RNA-binding protein and a translational regulator most well known for its role in spinocerebellar ataxia type 2 [37, 58, 59]. Atx2 displays a modest rhythm in the LNvs, consistent with clock control (S2 Fig; gammaBH = 0.045).…”

“…Of note Atx2 can also repress translation via an alternative TYF-independent pathway to control rhythms in the LNv [36]. This alternative pathway involves miRNA-mediated silencing [37] and may function with the Drosophila homolog of the Fragile Mental Retardation gene Fmr1 [38, 39].…”

A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

“…Protocadherin alpha 6 (PCDHA6) that belongs to the protocadherin alpha gene cluster encoding integral plasma membrane proteins, most likely plays a role in the synapsis formation and function in the brain (reviewed in Hamada and Yagi, 2001). Ataxin 2 (ATXN2) belongs to a group of genes associated with neurodegenerative diseases like amyotrophic lateral sclerosis, spinocerebellar ataxia-2, and Parkinson Disease (reviewed in Lee et al, 2018), while phospholipase C beta 1 (PLCB1) has been related to traits like epilepsy, depression, and AD (reviewed in Yang et al, 2016) and the Ras And Rab Interactor 3 (RIN3) has been linked to AD and dementia (Rasmussen et al, 2019). Animal models of PBX1 (PBX Homeobox 1) have pointed to Parkinson's disease (Villaescusa et al, 2016).…”