Rubinsztein Lab

Clearance of toxic proteins in neurodegeneration

Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s, are associated with the accumulation of particular proteins that form clumps because they are not folded properly. 

The goal of the Rubinsztein Lab is to understand the links between these diseases and autophagy — the bulk recycling process that degrades proteins and particular parts of the cell. The team is focused on understanding how autophagy is regulated using several cell and animal models, and possible ways to ramp up this process in order to remove toxic proteins and avoid the development of neurodegenerative disease. 

Non-autophagic roles of autophagy proteins in neurodegeneration

Prof Rubinsztein's research aims to advance understanding of autophagy to elucidate disease mechanisms and uncover therapeutic targets for neurodegenerative diseases. His work investigates intracellular protein misfolding and aggregation in conditions such as Alzheimer’s, Parkinson’s, tauopathies, and polyglutamine expansion diseases, including Huntington’s disease and spinocerebellar ataxias. Central to his research is the study of macroautophagy, a bulk degradation process that clears proteins and organelles, and its role in regulating aggregate-prone protein levels.

A significant discovery from the Rubinsztein Lab is that autophagy regulates the levels of intracytoplasmic aggregate-prone proteins, impacting neurodegenerative conditions like Huntington’s and Parkinson’s disease. David's team found that mutations causing these diseases often compromise autophagy, contributing to neurotoxicity and aggregate formation. This led to the introduction of the concept of non cell-autonomous autophagy compromise. Furthermore, his research has shown that toxicity of these proteins can be alleviated by enhancing their removal by autophagy in models of Huntington’s disease and related disorders. Notably, the team identified that inhibiting CCR5 with the FDA-approved drug maraviroc is neuroprotective, suggesting repurposing possibilities for this drug.

Current research efforts in David's lab include investigating non-autophagic roles of autophagy proteins. For example, they are examining how mutations in the autophagy protein WIPI4 enhance cell death via ferroptosis, independent of autophagy. Additionally, the team is exploring the signals that regulate autophagosome formation, focusing on the role of endocytic processes and the RAB11A recycling endosome compartment in capturing substrates for degradation.

Prof Rubinsztein's team is dedicated to leveraging these insights into autophagy biology to elucidate disease mechanisms and identify new therapeutic targets for neurodegenerative diseases.