Title: Reversing aggregates in neurodegeneration with the ubiquitin-proteasome system
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. Aggregation of amyloidogenic proteins, such as tau and alpha-synuclein, are implicated in Alzheimer's and Parkinson's disease, respectively. Removal of these toxic protein aggregates to reduce cell stress is important to prevent progression of the neurodegenerative processes. While much research has focused on how aggregates are assembled, relatively little is known about the reverse process of aggregate removal. The ubiquitin-proteasome system (UPS) is responsible for selective protein degradation, thus preventing aggregate formation. Our recent research has further suggested that proteasomes may also target aggregates in vitro (Cliffe et al.) and in model mammalian cell lines (Zhang et al.). Single-cell patch-clamp and nanopipette aggregate delivery methods further found that cellular proteasomes actively respond to cell stress in a cytoskeleton-dependent manner (Zhang et al). Using a multi-disciplinary approach that combines state-of-the-art fluorescence microscopy with CRISPR-Cas9 gene-editing techniques, neurobiology approaches and established proteasome biochemistry, our research direction is uniquely placed to investigate how proteasomes maintain cell homeostasis by targeting aggregates at distinct localisations. The main objective of my research programme is to investigate proteasome distribution and function in response to cell stress to restore homeostasis. The activity of proteasomes controls a wide range of processes including DNA repair, immune system activation, cell cycle and prevention of protein aggregation. It is currently unclear how proteasomes respond to cell stress and damage caused by toxic aggregates. Proteasomes are traditionally thought to diffuse throughout the cell to selectively degrade proteins and maintain homeostasis. Others and our recent data have further suggested that proteasome localisation can also be dynamic in space and in time, and translocation may occur through both diffusion and active transport. Despite the importance of proteasome dynamics in cells and the various regulatory roles associated with the proteasome, little is known about the biological mechanisms and associated protein partners that help to drive proteasome translocation to target its substrate. The research programme evolves around the following topics: • What are the factors that recruit proteasomes to distinct cellular locations and their functional role? • How are proteasomes transported inside neurons and when aggregates are present? • Which are the proteasomal responses to proteotoxic stress upon aggregate entry? Together, our research will ultimately unveil novel pathways and processes involved in aggregate clearance and how their malfunction may accelerate neurodegeneration leading up to dementia. Understanding such processes will provide unique approaches to therapeutically intervene neurodegeneration at distinct stages of disease progression.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL