Редактирование: DDI2 (раздел)

==Publications==

{{medline-entry
|title=Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29809168
|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 [[AR]]113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in [[AR]]113Q 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 [[AR]]113Q 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 [[AR]]113Q 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.
|mesh-terms=* Aging
* Animals
* Cell Adhesion Molecules
* Intracellular Signaling Peptides and Proteins
* Male
* Mice
* Mice, Transgenic
* Muscle, Skeletal
* Muscular Atrophy, Spinal
* Nuclear Respiratory Factor 1
* Peptides
* Proteasome Endopeptidase Complex
* Receptors, Androgen
* Trinucleotide Repeat Expansion
|keywords=* Muscle Biology
* Neuromuscular disease
* Neuroscience
* Protein misfolding
* Ubiquitin-proteosome system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063498
}}