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Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance

Lidia Wrobel1,2, Sandra M Hill1,2,3, Alvin Djajadikerta1,2

  • 1Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, United Kingdom.

Nature Communications
|July 16, 2022
PubMed

Insights

Activating VCP/p97 with compounds like SMER28 enhances the clearance of toxic proteins implicated in neurodegenerative diseases. This dual-action approach targets both proteasomal and lysosomal pathways for improved therapeutic outcomes.

Area of Science:

  • Neurobiology
  • Molecular Biology
  • Pharmacology

Background:

  • Neurodegenerative diseases like Huntington's disease involve toxic protein aggregation.
  • Targeting protein clearance pathways is a key therapeutic strategy.
  • Preferential clearance of mutant proteins over wild-type is desirable.

Purpose of the Study:

  • To identify therapeutic strategies for clearing aggregate-prone toxic proteins.
  • To investigate the role of VCP/p97 activators in protein degradation.
  • To assess the potential of VCP/p97 activation for neurodegenerative diseases.

Main Methods:

  • Utilized small molecule VCP/p97 activators, such as SMER28.
  • Investigated the activation of D1 ATPase activity of VCP/p97.
  • Examined the impact on both ubiquitin-proteasome and autophagy-lysosome pathways.
  • Assessed effects on autophagosome biogenesis and PI(3)P production.

Main Results:

  • Compounds activating VCP/p97 D1 ATPase activity enhance toxic protein removal.
  • SMER28 activates autophagosome biogenesis by modulating PI3K complex interactions.
  • VCP/p97 activators accelerate VCP-dependent proteasomal clearance of substrates.
  • This approach shows potential for clearing both monomeric and oligomeric protein species.

Conclusions:

  • VCP/p97 activation represents a promising therapeutic target for neurodegenerative diseases.
  • Dual activation of proteasomal and lysosomal pathways offers broad substrate clearance.
  • Small molecule activators like SMER28 provide a potential therapeutic avenue.

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