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Funder: UK Dementia Research Institute, Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.

Supplemental material, sj-pdf-1-jbx-10.1177_2472555220975358 for Regenerable Biosensors for Small-Molecule Kinetic Characterization Using SPR by Anders Gunnarsson, Christopher J. Stubbs, Philip B. Rawlins, Eleanor Taylor-Newman, Wei-chao Lee, Stefan Geschwindner, Vesa Hytönen, Geoffrey Holdgate, Rupam Jha and Göran Dahl in SLAS Discovery