title: Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.
abstract: Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, becoming proteolyzed to a smaller fragment through a process requiring the proteasome after it is incorporated into intranuclear inclusions. Moreover, the toxicity-predicting conformational antibody 3B5H10 bound to soluble full-length AR species but not to fragment-containing nuclear inclusions. These data suggest that the AR is toxic as a full-length protein, challenging the notion of polyglutamine protein fragment-associated toxicity by redefining the role of AR proteolysis in spinal and bulbar muscular atrophy pathogenesis.
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: Erin M
authors: EM
authors: Heine
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: Tamar R
authors: TR
authors: Berger
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: Anna
authors: A
authors: Pluciennik
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: Christopher R
authors: CR
authors: Orr
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors: Lori
authors: L
authors: Zboray
authors: From the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 Diane.merry@jefferson.edu.
authors: Diane E
authors: DE
authors: Merry
mesh_terms: D000818:Animals; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex
keywords: aggregation; androgen receptor; neurodegeneration; polyglutamine disease; proteasome