title: Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy.
abstract: The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role in pathogenesis. In SBMA, the nucleus is further implicated by the critical role for disease of androgens, which promote the nuclear translocation of the mutant androgen receptor (AR). To clarify the importance of the nucleus in SBMA, we genetically manipulated the nuclear localization signal of the polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with SBMA mice. While we found that nuclear localization of polyglutamine-expanded AR is required for SBMA, we also discovered, using cell models of SBMA, that it is insufficient for both aggregation and toxicity and requires androgens for these disease features. Through our studies of cultured motor neurons, we further found that the autophagic pathway was able to degrade cytoplasmically retained expanded AR and represents an endogenous neuroprotective mechanism. Moreover, pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. Thus, our studies firmly establish that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. They also highlight a mechanistic basis for the requirement for nuclear localization in SBMA neurotoxicity, namely the lack of mutant AR removal by the autophagic protein degradation pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Montie
authors.forename: Maria S
authors.initials: MS
authors.lastname: Cho
authors.forename: Latia
authors.initials: L
authors.lastname: Holder
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019913:Nuclear Localization Signals / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: D000728:Androgens; D019913:Nuclear Localization Signals; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine