SMER28 binding to VCP/p97 enhances both autophagic and proteasomal neurotoxic protein clearance.

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Wrobel, Lidia 
Hill, Sandra M 
Rubinsztein, David C 

The ability to maintain a functional proteome by clearing damaged or misfolded proteins is critical for cell survival, and aggregate-prone proteins accumulate in many neurodegenerative diseases, such as Huntington, Alzheimer, and Parkinson diseases. The removal of such proteins is mainly mediated by the ubiquitin-proteasome system and autophagy, and the activity of these systems declines in disease or with age. We recently found that targeting VCP/p97 with compounds like SMER28 enhances macroautophagy/autophagy flux mediated by the increased activity of the PtdIns3K complex I. Additionally, we found that SMER28 binding to VCP stimulates aggregate-prone protein clearance via the ubiquitin-proteasome system. This concurrent action of SMER28 on both degradation pathways resulted in the selective decrease in disease-causing proteins but not their wild-type counterparts. These results reveal a promising mode of VCP activation to counteract the toxicity caused by aggregate-prone proteins.

Aggregate-prone proteins, PI3P, SMER28, VCP/p97, autophagy activation, ubiquitin–proteasome system, Proteasome Endopeptidase Complex, Cell Cycle Proteins, Valosin Containing Protein, Adenosine Triphosphatases, Autophagy, Ubiquitin
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Informa UK Limited
We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (UKDRI-2002 to DCR), The Tau Consortium, Alzheimer’s Research UK, an anonymous donation to the Cambridge Centre for Parkinson-Plus, AstraZeneca, the Swedish Natural Research Council (VR) (reference 2016–06605; to S.M.H;) and from the European Molecular Biology Organisation (EMBO long-term fellowships, ALTF 1024-2016 and ALTF 135-2016, to SMH and LW; respectively).