Delineating the role of defects in the ubiquitin--proteasome system in MND

About the project

The Ubiquitin-Proteasome system (UPS) is the major cellular mechanism for clearing unwanted proteins from the cell. Together with the autophagy system, the UPS provides the majority of targeted proteolytic activity and is also involved in degrading mis-folded and aggregating proteins.

Work in recent years has highlighted the role of the UPS in the development of MND, when mutations in Ubiquilin-2, a regulator of the ubiquitin system, were shown to cause some familial cases of MND.

Our previous research has focused on elucidating the defects caused by the mutation, and we found that when Ubiquilin-2 is mutated, the ability of the UPS to clear aggregating proteins is diminished. Currently, we are trying to understand the mechanism behind the role Ubiquilin-2 in aggregate clearance with a focus on identifying new partners and regulators, as well as druggable nodes that may enhance the ability of cells to clear misfolded proteins.


MND Scotland


Hjerpe R, Bett JS, Keuss MJ, Solovyova A, McWilliams TG, Johnson C, Sahu I, Varghese J, Wood N, Wightman M, Osborne G, Bates GP, Glickman MH, Trost M, Knebel A, Marchesi F, Kurz T
UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome
Cell. 2016 Aug 11;166(4):935-949

Primary location


Principal Investigator

Other people involved

George Gorrie

Matthew Keuss