title: Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, 208 Bluemle Life Sciences Building, 233 S. 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Bailey
authors.forename: Isabella F M
authors.initials: IF
authors.lastname: Andriola
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005091:Exons; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006207:Half-Life; D006360:Heat-Shock Proteins / Q000378:metabolism; D006822:Hybrid Cells; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D011099:Polyglutamic Acid / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D019680:Trinucleotide Repeat Expansion
chemical_list: D015853:Cysteine Proteinase Inhibitors; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011944:Receptors, Androgen; D011994:Recombinant Proteins; C067713:lactacystin; D011099:Polyglutamic Acid; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000111:Acetylcysteine