Investigating cell type specific defects in protein quality control across the genetic landscape of Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease without cure. Today >20 genes have been linked to familial PD of which most are involved in various aspects of protein quality control. But it is unclear how these defects ultimately manifest in overlapping pathology.
Intriguingly, several different PD fly models show similar transcriptome changes in defined single cell in the brains of young animals. The deregulated genes mainly affect protein homeostasis and neuronal dysfunction is rescued by increasing protein turnover.
I therefore speculate that different PD mutations converge on a common hub that impairs proteostasis, driving early neuronal dysfunction.
To investigate my hypothesis, I will source a unique Drosophila collection containing all known PD mutations. I will assess how PD mutations affect the proteostasis globally and in synapses. I will determine common vulnerability pathways by combining fly genetics and biochemical assays with single cell RNA sequencing. Finally, I will validate these central hubs in iPSC derived neurons from patients with the corresponding PD mutations.
I will thus identify the common hubs in cell type specific vulnerability pathways that are deregulated early in disease across several PD mutations.
My project will deliver 3 important results: 1. obtain innovative therapeutic targets to modify disease progression, 2. reveal how proteostasis maintains synaptic function and 3. answer why this process is affected early in PD.