Abstract
Altered protein homeostasis underlies degenerative diseases triggered by misfolded proteins, including spinal and bulbar muscular atrophy (SBMA), a neuromuscular disorder caused by a CAG/glutamine expansion in the androgen receptor. Here we show that the unfolded protein response (UPR), an ER protein quality control pathway, is induced in skeletal muscle from SBMA patients, AR113Q knock-in male mice, and surgically denervated wild-type mice. To probe the consequence of UPR induction, we deleted CHOP (C/EBP homologous protein), a transcription factor induced following ER stress. CHOP deficiency accentuated atrophy in both AR113Q and surgically denervated muscle through activation of macroautophagy, a lysosomal protein quality control pathway. Conversely, impaired autophagy due to Beclin-1 haploinsufficiency decreased muscle wasting and extended lifespan of AR113Q males, producing a significant and unexpected amelioration of the disease phenotype. Our findings highlight critical cross-talk between the UPR and macroautophagy, and they indicate that autophagy activation accentuates aspects of the SBMA phenotype.
Highlights
Many adult onset neurodegenerative disorders are characterized by the accumulation of abnormally folded proteins that selfassociate into soluble oligomeric species or coalesce into insoluble protein aggregates
In spinal and bulbar muscular atrophy (SBMA), the mutant androgen receptor with an expanded glutamine tract undergoes hormone-dependent nuclear translocation, unfolding, and oligomerization—steps that are critical to the development of progressive proximal limb and bulbar muscle weakness in men
We show that the unfolded protein response (UPR), an endoplasmic reticulum stress response, is triggered in skeletal muscle from SBMA patients and knock-in mice
Summary
Many adult onset neurodegenerative disorders are characterized by the accumulation of abnormally folded proteins that selfassociate into soluble oligomeric species or coalesce into insoluble protein aggregates. Spinal and bulbar muscular atrophy (SBMA), a member of this group, is a progressive neuromuscular disorder caused by an expanded glutamine tract near the amino terminus of the androgen receptor (AR) [3] This mutation leads to hormone-dependent AR unfolding, and to the predominant loss of lower motor neurons in the brainstem and spinal cord of affected males. Clinical onset occurs in adolescence to adulthood and is characterized initially by muscle cramps and elevated serum creatine kinase [4,5] These myopathic features commonly precede muscle weakness, which inevitably develops as the disease progresses and is most severe in the proximal limb and bulbar muscles. Late in the course of disease, the pathologic features of SBMA include loss of motor neurons in the brainstem and spinal cord and the occurrence of myopathic and neurogenic changes in skeletal muscle [6,7]
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