Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/VCP-associated disease

Area of Science:

• Molecular biology
• Cell biology
• Neuroscience

Background:

• Mutations in p97/VCP (valosin-containing protein) are linked to inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD).
• p97/VCP, an AAA+ ATPase, plays a role in protein degradation pathways, and IBMPFD is characterized by ubiquitinated inclusions.
• Dysfunctional protein degradation is a hallmark of IBMPFD, suggesting a link between p97/VCP mutations and cellular proteostasis disruption.

Purpose of the Study:

• To investigate the impact of IBMPFD-associated p97/VCP mutations on protein aggregation and degradation pathways.
• To explore the role of protein aggregate trafficking and the potential therapeutic benefit of HDAC6 in IBMPFD.

Main Methods:

• Utilized cell culture models expressing IBMPFD mutant p97/VCP.
• Co-expressed aggregate-prone proteins (expanded polyglutamine) to study inclusion body formation.
• Assessed protein ubiquitination, proteasome inhibition susceptibility, and aggresome localization.
• Investigated the interaction with HDAC6 and its effect on aggregate clearance and cell survival.

Main Results:

• IBMPFD mutant p97/VCP expression increased ubiquitinated proteins and sensitivity to proteasome inhibitors.
• Expanded polyglutamine proteins formed small inclusions that failed to co-localize with autophagic machinery in IBMPFD mutant cells.
• IBMPFD mutants interfered with the trafficking of these inclusions to aggresomes.
• HDAC6 expression rescued aggresome formation, promoted autophagic degradation of aggregates, and protected cells from polyglutamine-induced death.

Conclusions:

• p97/VCP mutations disrupt protein aggregate trafficking and degradation, contributing to IBMPFD pathogenesis.
• Targeting protein aggregate inclusion body formation and trafficking, potentially via HDAC6, offers a therapeutic strategy for IBMPFD and related proteinopathies.