Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue

Abstract

During cell stress, the transcription and translation of immediate early genes are prioritized, while most other messenger RNAs (mRNAs) are stored away in stress granules or degraded in processing bodies (P-bodies). TIA-1 is an mRNA-binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Because other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1, and HNRNPA1 are crucial for the motor neuron diseases amyotrophic lateral sclerosis (ALS)/spinal muscular atrophy (SMA) and for the frontotemporal dementia (FTD), here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to +2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb vs. decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent +3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2 vs. a −2.4-fold downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison, subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain, similar to the fasting effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-014-0397-x) contains supplementary material, which is available to authorized users.

Frequent hepatic steatosis in amyotrophic lateral sclerosis: Implication for systemic involvement

“…Mutated SOD1 model mice showed prominent inflammatory responses in the liver such as natural killer‐T cells and abnormal insulin‐like growth factor‐1 axis along with lipid redistribution . Genetic deletion of Tardbp (encoding TDP‐43) also led to dysregulated lipid homeostasis . It should be recognized, however, that animal models for ALS might not properly reflect the molecular and metabolic dysfunction in patients with ALS.…”

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

“…However, it is not known if FTD/ALS patients carrying TIA1 mutations display SMN exon 7 skipping in any of their tissues. Notably, nervous tissue of Tia1 knockout mouse shows dysregulated expression of lipid storage and membrane dynamics factors [103]. However, effect of Tia1 deletion on SMN2 exon 7 splicing cannot be evaluated because mice lack SMN2 .…”

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

“…The structure of the human ATXN2 protein is characterized (1) by the N-terminal polyQ domain (5), (2) by dispersed proline-rich-domains that mediate association with various SH3-motif containing proteins of the tyrosine kinase receptor endocytosis machinery and thus modulate neuro-trophic signaling (6, 7), (3) by a C-terminal PAM2 motif that mediates interaction with the poly(A)-binding protein PABPC1 that is crucial for mRNA translation (8) and (4) by Lsm and Lsm-AD sequences that mediate the association with RNAs (9 -11). ATXN2 is normally localized at the rough endoplasmic reticulum (12), but it relocalizes during periods of low cell energy together with PABPC1 to stress granules where the quality control of RNA occurs (3) and where fasting responses are modulated (13). The suppression of Ataxin-2 in mice and flies modulates mRNA translation and circadian clock (4, 14 -16).…”