Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis.

Authors

Erin M Heine, Thomas Jefferson UniversityFollow
Tamar R Berger, Thomas Jefferson UniversityFollow
Anna Pluciennik, Thomas Jefferson UniversityFollow
Christopher R Orr, Thomas Jefferson UniversityFollow
Lori Zboray, Thomas Jefferson UniversityFollow
Diane E Merry, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-15-2015

Comments

This is the final published version of the article from the Journal of Biological Chemistry, 2015 May 15;290(20):12572-84.

The full text of the article can also be accessed at the journal's website: https://doi.org/10.1074/jbc.M114.617894

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.

Recommended Citation

Heine, Erin M; Berger, Tamar R; Pluciennik, Anna; Orr, Christopher R; Zboray, Lori; and Merry, Diane E, "Proteasome-mediated proteolysis of the polyglutamine-expanded androgen receptor is a late event in spinal and bulbar muscular atrophy (SBMA) pathogenesis." (2015). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 206.
https://jdc.jefferson.edu/bmpfp/206

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

25795778

Language

English