title: p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model.
abstract: Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR.
authors: Department of Neurology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
authors: Hideki
authors: H
authors: Doi
authors: Hiroaki
authors: H
authors: Adachi
authors: Masahisa
authors: M
authors: Katsuno
authors: Makoto
authors: M
authors: Minamiyama
authors: Shinjiro
authors: S
authors: Matsumoto
authors: Naohide
authors: N
authors: Kondo
authors: Yu
authors: Y
authors: Miyazaki
authors: Madoka
authors: M
authors: Iida
authors: Genki
authors: G
authors: Tohnai
authors: Qiang
authors: Q
authors: Qiang
authors: Fumiaki
authors: F
authors: Tanaka
authors: Toru
authors: T
authors: Yanagawa
authors: Eiji
authors: E
authors: Warabi
authors: Tetsuro
authors: T
authors: Ishii
authors: Gen
authors: G
authors: Sobue
mesh_terms: D000368:Aged; D000818:Animals; D001343:Autophagy / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000175:diagnosis / Q000209:etiology; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection
chemical_list: C490981:Gtf2h1 protein, mouse; D010455:Peptides; D011944:Receptors, Androgen; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; C097188:polyglutamine
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