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

The Journal of Biological Chemistry
Erin M HeineDiane E Merry

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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Citations

Nov 18, 2015·Journal of Molecular Neuroscience : MN·Paola RusminiAngelo Poletti
Jun 10, 2020·International Journal of Molecular Sciences·Fiona LimanaqiFrancesco Fornai
Apr 8, 2017·Frontiers in Neuroscience·E F E KuiperSteven Bergink
Nov 7, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Frederick J Arnold, Diane E Merry
Nov 11, 2020·The Journal of Clinical Investigation·Anna PluciennikDiane E Merry

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