Abstract
Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the Drosophila brain and S2 cells. Atx2 interactions with AU-rich elements in 3'UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.
Highlights
Ataxin-2’s involvement in human disease, its relevance for therapeutics development and its established roles in mRNP-phase transitions, cell physiology, metabolic control and animal behavior, have led to considerable interest in understanding molecular mechanisms by which the protein functions
In elav-Gal4; TubGal80ts, UAS-Atx2-ADARcd adult flies shifted from 18°C to 29oC for 5 days shortly after eclosion, neural mRNAs expressed in adult flies would be susceptible to editing at adenosine residues proximal to Atx2 binding sites
Previous work has shown that Drosophila Atx2 functions in neurons as a translational activator of the period mRNA that controls circadian rhythms, as a translational repressor of the calciumcalmodulin dependent kinase CaMKII involved in synaptic plasticity and memory (Lim and Allada, 2013; Sudhakaran et al, 2014; Zhang et al, 2013)
Summary
Ataxin-2’s involvement in human disease, its relevance for therapeutics development and its established roles in mRNP-phase transitions, cell physiology, metabolic control and animal behavior, have led to considerable interest in understanding molecular mechanisms by which the protein functions. Ataxin-2 positively or negatively regulates the translation of specific mRNAs (Lee et al, 2017; Lim and Allada, 2013; McCann et al, 2011; Zhang et al, 2013). At an organismal level, the protein regulates metabolism, circadian rhythm and the consolidation of long-term memory (Bakthavachalu, Huelsmeier et al, 2018; Lim and Allada, 2013; Meierhofer et al, 2016; Pfeffer et al, 2017; Zhang et al, 2013). Parallel clinical genetic studies have shown that genetic mutations in human Ataxin-2 (Atxn2) can cause the hereditary neurodegenerative diseases spinocerebellar ataxia type II (SCA2) or amyotrophic lateral sclerosis (ALS) (Daoud et al, 2011; Elden et al, 2010; Lastres-becker et al, 2007; Lee et al, 2011; Scoles and Pulst, 2018; Wadia, 1977; Wadia and Swami, 1971), and subsequent work showing that genetic reduction of Ataxin-2 activity slows neurodegeneration in animal models of ALS has inspired the design and development of therapeutics targeting human Ataxin-2 (Becker et al, 2017; Becker and Gitler, 2018; Elden et al, 2010; Scoles et al, 2017)
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