ArticleThe Journal of clinical investigation2018
Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- Androgen receptor imprints satellite cell stemness and preserves their reservoir for lifelong regeneration and optimal repair.Science advances · 2026Article
- Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs.ACS pharmacology & translational science · 2025Review
- Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy.JCI insight · 2024Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases.Biology · 2023Review
- Identification of Immune-Linked Hub Genes and Diagnostic Model Construction in Schizophrenia.Journal of molecular neuroscience : MN · 2023Article
- Review
- AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.Acta neuropathologica · 2022Article
- Exploring the Role of Posttranslational Modifications in Spinal and Bulbar Muscular Atrophy.Frontiers in molecular neuroscience · 2022Review
- The role of ubiquitination in spinal and bulbar muscular atrophy.Frontiers in molecular neuroscience · 2022Review
- Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity.Science advances · 2021Article
- MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease.Acta neuropathologica · 2020Article
- Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.International journal of molecular sciences · 2020Review
- Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases.Cellular and molecular life sciences : CMLS · 2020Review
- The first year.Acta neuropathologica · 2020Article
- Genetic approaches to the treatment of inherited neuromuscular diseases.Human molecular genetics · 2019Review
- Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy.Expert opinion on therapeutic targetsReview
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.