Compounds Activating VCP D1 ATPase Enhance Both Autophagic and Proteasomal Neurotoxic Protein Clearance

Lidia Wrobel, Sandra M. Hill, Alvin Djajadikerta, Marian Fernandez-Estevez, Cansu Karabiyik, Avraham Ashkenazi, Victoria J. Barratt, Eleanna Stamatakou, Anders Gunnarsson, Timothy Rasmusson, Eric W. Miele, Nigel Beaton, Roland Bruderer, Yuehan Feng, Lukas Reiter, M. Paola Castaldi, Rebecca Jarvis, Keith Tan, Roland W. Bürli & David C. Rubinsztein. Nature Communications

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. This study shows how a compound binding to VCP D1 ATPase enhances proteasomal neurotoxic protein clearance. Furthermore, our proprietary High-Resolution Limited Proteolysis (HR-LiP) technology was used to 3D-map the binding site of the compound under investigation for potential use in neurodegenerative diseases. As a result, we could confidently validate the binding site on the target and explain the observed phenotype.

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