Establishing how and why protein aggregates escape molecular chaperones in the context of MND

Discovery Grant
The key goal of our work is to resolve a critical unknown in the MND research field - how and why do molecular chaperones become overwhelmed in the context of MND and is boosting chaperone activity a viable therapeutic strategy for the treatment of MND?
Hypothesis: Molecular chaperones with enhanced capacity to inhibit protein aggregation and promote cell viability are a therapeutic target. We will identify and characterise these molecular chaperones as a key step towards a potential treatment for MND.
Aims: The specific aims of this project are to:
1. Screen the chaperome (the family of chaperones) to identify chaperone isoforms that are most effective
at inhibiting the aggregation of MND-related proteins and promoting cell viability;
2. Validate the capacity of these chaperones to reduce MND-related protein pathology and improve motor function in cell and animal models of MND; and
3. Establish the sequence motifs within chaperones that are responsible for their capacity to interact with MND-related aggregation-prone proteins to reduce proteotoxicity