Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP-associated disease.
Mutations in p97/VCP cause the multisystem disease inclusion body myopathy, Paget disease of the bone and frontotemporal dementia (IBMPFD). p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and has been implicated in multiple cellular processes. One pathologic feature in IBMPFD is ubiquitinated inclusions, suggesting that mutations in p97/VCP may affect protein degradation. The present study shows that IBMPFD mutant expression increases ubiquitinated proteins and susceptibility to proteasome inhibition. Co-expression of an aggregate prone protein such as expanded polyglutamine in IBMPFD mutant cells results in an increase in aggregated protein that localizes to small inclusions instead of a single perinuclear aggresome. These small inclusions fail to co-localize with autophagic machinery. IBMPFD mutants avidly bind to these small inclusions and may not allow them to traffic to an aggresome. This is rescued by HDAC6, a p97/VCP-binding protein that facilitates the autophagic degradation of protein aggregates. Expression of HDAC6 improves aggresome formation and protects IBMPFD mutant cells from polyglutamine-induced cell death. Our study emphasizes the importance of protein aggregate trafficking to inclusion bodies in degenerative diseases and the therapeutic benefit of inclusion body formation.
Ju
Jeong-Sun
JS
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Miller
Sara E
SE
Hanson
Phyllis I
PI
Weihl
Conrad C
CC
D000251:Adenosine Triphosphatases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D002479:Inclusion Bodies; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000737:chemistry; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D010455:Peptides; D025801:Ubiquitin; C097188:polyglutamine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse