Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.
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| 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.
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| Authors | Erin M Heine, Tamar R Berger, Anna Pluciennik, Christopher R Orr, Lori Zboray, Diane E Merry |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 20 Pg. 12572-84 (May 15 2015) ISSN: 1083-351X [Electronic] United States |
| PMID | 25795778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Copyright | © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. |
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