RT Journal Article
SR Electronic
T1 p62/SQSTM1 Differentially Removes the Toxic Mutant Androgen Receptor via Autophagy and Inclusion Formation in a Spinal and Bulbar Muscular Atrophy Mouse Model
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7710
OP 7727
DO 10.1523/JNEUROSCI.3021-12.2013
VO 33
IS 18
A1 Hideki Doi
A1 Hiroaki Adachi
A1 Masahisa Katsuno
A1 Makoto Minamiyama
A1 Shinjiro Matsumoto
A1 Naohide Kondo
A1 Yu Miyazaki
A1 Madoka Iida
A1 Genki Tohnai
A1 Qiang Qiang
A1 Fumiaki Tanaka
A1 Toru Yanagawa
A1 Eiji Warabi
A1 Tetsuro Ishii
A1 Gen Sobue
YR 2013
UL http://www.jneurosci.org/content/33/18/7710.abstract
AB 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.