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- Title
Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.
- Authors
Petrauskas, Arnas; Fortunati, Daniel L.; Kandi, Arvind Reddy; Pothapragada, Sai Shruti; Agrawal, Khushboo; Singh, Amanjot; Huelsmeier, Joern; Hillebrand, Jens; Brown, Georgia; Chaturvedi, Dhananjay; Lee, Jongbo; Lim, Chunghun; Auburger, Georg; VijayRaghavan, K.; Ramaswami, Mani; Bakthavachalu, Baskar
- Abstract
Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Transgenic Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration. Author summary: Mutations in genes that promote protein aggregation are primarily associated with neurodegenerative diseases. RNA-binding proteins, crucial for gene regulation and cellular stress response, are also major constituents of protein aggregate-rich mRNP granules. Recent studies aim to understand the molecular mechanisms governing the formation of stress granules identified Intrinsically Disordered Regions (IDRs) within mRNP granule proteins as a key factor that facilitates the formation of amyloid-like structures. A deeper understanding of stress granule dynamics holds promise for elucidating neurodegenerative disease mechanisms. Ataxin-2, is an RNA-binding protein implicated in neurodegenerative disorders like spinocerebellar ataxia type II, amyotrophic lateral sclerosis, and Parkinsonism. Reducing the levels of Ataxin-2 levels or deleting its IDR prevents RNP aggregation and offers neuroprotection in animal models of neurodegenerative diseases. We show that deleting the structured LSm domain of Ataxin-2, which impedes granule assembly, enhances cytotoxicity. Moreover, specific molecular interactions involving Ataxin-2 PAM2 motif binding to polyA-binding protein is crucial for recruiting mRNAs and other proteins into RNP granules. These interactions not only shape granule composition but also influence disease progression. Our findings propose a model illustrating the dynamic remodeling of Ataxin-2 interactions, emphasizing the distinct roles of structured and unstructured domains in governing mRNP-granule condensation and neurodegeneration.
- Subjects
RNA-binding proteins; AMYOTROPHIC lateral sclerosis; STRESS granules; SPINOCEREBELLAR ataxia; GENETIC regulation; MESSENGER RNA
- Publication
PLoS Genetics, 2024, Vol 20, Issue 5, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1011251