Huntington's Disease Protein Huntingtin Associates with its own mRNA

Journal of Huntington's Disease
Brady P CulverNaoko Tanese

Abstract

The Huntington's disease (HD) protein huntingtin (Htt) plays a role in multiple cellular pathways. Deregulation of one or more of these pathways by the mutant Htt protein has been suggested to contribute to the disease pathogenesis. Our recent discovery-based proteomics studies have uncovered RNA binding proteins and translation factors associated with the endogenous Htt protein purified from mouse brains, suggesting a potential new role for Htt in RNA transport and translation. To investigate how Htt might affect RNA metabolism we set out to purify and analyze RNA associated with Htt. RNA was extracted from immunopurified Htt-containing protein complexes and analyzed by microarrays and RNA-Seq. Surprisingly, the most enriched mRNA that co-purified with Htt was Htt mRNA itself. The association of Htt protein and Htt mRNA was detected independent of intact ribosomes suggesting that it is not an RNA undergoing translation. Furthermore, we identified the recently reported mis-spliced Htt mRNA encoding a truncated protein comprised of exon 1 and a portion of the downstream intron in the immunoprecipitates containing mutant Htt protein. We show that Htt protein co-localizes with Htt mRNA and that wild-type Htt reduces expression of ...Continue Reading

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Citations

May 30, 2019·Molecular & Cellular Proteomics : MCP·Karen A SapEric A Reits
Oct 11, 2019·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Shinichiro MoriToru Iwaki
Mar 25, 2017·Journal of Huntington's Disease·Jeh-Ping Liu, Scott O Zeitlin
Dec 5, 2019·Cellular and Molecular Life Sciences : CMLS·Hiranmay JoagAmitabha Majumdar
Sep 1, 2019·Molecular & Cellular Proteomics : MCP·Karen A SapEric A Reits

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Methods Mentioned

BETA
RNA-seq
affinity purifications
immunoprecipitations
PCR
transfections
affinity purification
cross-linking immunoprecipitation
pull down
transgenic

Software Mentioned

Adobe Photoshop
MEME
HTSeq
STAR
DEXSeq R package
Illumina Bcl2FastQ

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