Mapping the proteome vulnerable to unfolding and aggregation under proteostasis stress

Project Details

A healthy state of protein homeostasis (proteostasis) requires balance in the cellular mechanisms that control the synthesis, folding, clearance and transport processes of proteins. In the major neurodegenerative diseases, including Motor Neuron, Huntington, Parkinson, and Alzheimer, these systems become defective providing a heightened probability for unresolved clearance of misfolded proteins, which aggregate, mislocalise and more broadly disturb the physiology of cells. A major gap in our knowledge is a systematic understanding of how the proteome becomes compromised in foldedness or aggregation state as disease manifests.

The aims of this project include determining which proteins in the proteome are particularly susceptible to misfolding and aggregation under proteostasis challenge. Defining these proteins offers rich potential for new therapeutic targets since they would be prime candidates as causative agents in the molecular cascade of dysfunction. In addition, the project will determine whether the proteomes susceptible to misfolding and aggregation are inherently metastable to all stress or are selectively altered by distinct challenges to proteostasis. Third the goal is to determine how proteomes behave in different cell types under stress. This is important to determine because there is evidence that neurons are selectively vulnerable to degeneration under conditions of proteostasis imbalance caused by misfolded proteome accumulation.

This project will use state of the art quantitative proteomics and neuron cell culture models.  The project will also employ CRISPR-Cas9 gene editing technologies.