Petrauskas, A., Fortunati, D.L., Kandi, A.R., Pothapragada, S.S., Agrawal, K., Singh, A., Huelsmeier, J., Hillebrand, J., Brown, G., Chaturvedi, D., Lee, J., Lim, C., Auburger, G., VijayRaghavan, K., Ramaswami, M., Bakthavachalu, B. (2024). Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.  PLoS Genet. 20(5): e1011251.

FBrf0259727

Research paper

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. 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.

PMC11166328 (PMC) (EuropePMC)