Huntington’s Disease Protein Huntingtin Associates with its own mRNA
| Autor: | Brady P. Culver, Man-Shan Yu, Igor Dolgalev, Josh DeClercq, Adriana Heguy, Naoko Tanese, Bin Ma |
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| Rok vydání: | 2016 |
| Předmět: |
Research Report
0301 basic medicine Untranslated region congenital hereditary and neonatal diseases and abnormalities RNA-protein interaction mRNA translation Huntingtin animal diseases Mice Transgenic RNA-binding protein Biology Cell Line Mice 03 medical and health sciences Cellular and Molecular Neuroscience Exon huntingtin exon 1 mental disorders Huntingtin Protein Animals RNA Messenger Fmrp Visual Cortex Messenger RNA Sequence Analysis RNA Intron RNA Molecular biology nervous system diseases 3. Good health Huntington Disease 030104 developmental biology nervous system Neurology (clinical) Huntington’s disease |
| Zdroj: | Journal of Huntington's Disease |
| ISSN: | 1879-6400 1879-6397 |
| DOI: | 10.3233/jhd-150177 |
| Popis: | Background: 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. Objective: To investigate how Htt might affect RNA metabolism we set out to purify and analyze RNA associated with Htt. Methods: RNA was extracted from immunopurified Htt-containing protein complexes and analyzed by microarrays and RNA-Seq. Results: 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 a reporter construct harboring the Htt 3’ UTR. Conclusions: HD protein is found in a complex with its own mRNA and RNA binding proteins and translation factors. Htt may be involved in modulating its expression through post-transcriptional pathways. It is possible that Htt shares mechanistic properties similar to RNA binding proteins such as TDP-43 and FUS implicated in other neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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