Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction
Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2020
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| Online Access: | https://hdl.handle.net/1721.1/126010 |
| _version_ | 1811093702800572416 |
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| author | Nath, Samir R. Yu, Zhigang Gipson, Theresa A. Marsh, Gregory B. Yoshidome, Eriko Robins, Diane M. Todi, Sokol V. Housman, David E Lieberman, Andrew P. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Nath, Samir R. Yu, Zhigang Gipson, Theresa A. Marsh, Gregory B. Yoshidome, Eriko Robins, Diane M. Todi, Sokol V. Housman, David E Lieberman, Andrew P. |
| author_sort | Nath, Samir R. |
| collection | MIT |
| description | Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder. |
| first_indexed | 2024-09-23T15:49:18Z |
| format | Article |
| id | mit-1721.1/126010 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:49:18Z |
| publishDate | 2020 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | mit-1721.1/1260102022-10-02T04:20:02Z Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction Nath, Samir R. Yu, Zhigang Gipson, Theresa A. Marsh, Gregory B. Yoshidome, Eriko Robins, Diane M. Todi, Sokol V. Housman, David E Lieberman, Andrew P. Koch Institute for Integrative Cancer Research at MIT Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder. National Institutes of Health (Grant R01 NS055746) National Institutes of Health (Grant P30-CA14051) 2020-06-29T14:28:51Z 2020-06-29T14:28:51Z 2018-07 2017-12 2019-12-06T20:23:18Z Article http://purl.org/eprint/type/JournalArticle 0021-9738 1558-8238 https://hdl.handle.net/1721.1/126010 Nath, Samir R. et al. "Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction." Journal of Clinical Investigation 128, 8 (July 2018): 3630–3641 © 2018 American Society for Clinical Investigation en http://dx.doi.org/10.1172/jci99042 Journal of Clinical Investigation Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Society for Clinical Investigation Journal of Clinical Investigation |
| spellingShingle | Nath, Samir R. Yu, Zhigang Gipson, Theresa A. Marsh, Gregory B. Yoshidome, Eriko Robins, Diane M. Todi, Sokol V. Housman, David E Lieberman, Andrew P. Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title | Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title_full | Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title_fullStr | Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title_full_unstemmed | Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title_short | Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction |
| title_sort | androgen receptor polyglutamine expansion drives age dependent quality control defects and muscle dysfunction |
| url | https://hdl.handle.net/1721.1/126010 |
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