TY - JOUR A1 - Fittschen, Monica A1 - Lastres-Becker, Isabel A1 - Halbach, Melanie Vanessa A1 - Damrath, Ewa A1 - Gispert, Suzana A1 - Azizov, Mekhman A1 - Walter, Michael A1 - Müller, S. A1 - Auburger, Georg T1 - Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate T2 - Neurogenetics N2 - Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2−/−) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2−/− mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation. KW - Spinocerebellar ataxia KW - Amyotrophic lateral sclerosis KW - ATXN2 KW - RNA processing KW - Ribosomal translation KW - Ribosomal S6 phosphorylation KW - Global protein synthesis rates KW - Cellular stress Y1 - 2015 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/30633 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-306333 N1 - This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. VL - 16 SP - 181 EP - 192 PB - Springer CY - Berlin ; Heidelberg ER -