Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice.
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.
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Zhigang
Z
Yu
Adrienne M
AM
Wang
Hiroaki
H
Adachi
Masahisa
M
Katsuno
Gen
G
Sobue
Zhenyu
Z
Yue
Diane M
DM
Robins
Andrew P
AP
Lieberman
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics*; D003714:Denervation; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012584:Sciatic Nerve / Q000601:surgery; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP