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

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Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder. There is currently no cure, and only transient symptomatic treatments of the motor symptoms are available. If we want to tackle PD in its earliest stages and slow its progression, there is an urgent need for innovative therapeutics that modify the earliest non-motor symptoms that precede neuronal death. Unfortunately, this is hampered by insufficient knowledge on the origins of early neuronal defects. In this research project, I will address this knowledge gap to gain important insights into the molecular pathways, which are affected early in PD.More than 20 genes have been linked to familial forms of PD. Most “PD genes” are involved in various aspects of protein quality control, but it remains unclear how these diverse molecular defects ultimately manifest in an overlapping pathology.Drosophila melanogaster is an excellent model organism for studying neurodegenerative diseases as 70% of human disease genes are conserved in flies, and key features of PD pathology are recapitulated including early symptoms such as sleep disorders or impaired sense of smell.Intriguingly, a few PD fly models exhibit similar transcriptome changes in the same cell types in the brains of young animals. These deregulated genes mainly affect protein homeostasis pathways and neuronal dysfunction can be rescued by increasing the protein turnover capacity at synapses in the most affected cell types.Therefore, I speculate that different pathogenic PD variants generally converge onto a common central hub that deregulates protein quality control pathways in the presynaptic terminal early in the disease and that this contributes to the neuronal dysfunction that precedes neuronal death.In the proposed project, I will investigate this hypothesis by sourcing a unique Drosophila collection containing all known pathogenic PD mutations. I will assess how the PD mutations affect the cellular protein homeostasis network, both globally and locally, in synaptic terminals. I will determine common vulnerability pathways by combining versatile fly genetics and biochemical assays with state-of-the-art single cell RNA sequencing. Subsequently, I will validate the identified central hubs and mechanisms in induced pluripotent stem cell derived neurons from PD patients harboring the corresponding mutations.Thus, I will identify the common key factors in the cell type specific vulnerability pathways that are deregulated early in disease across the familial genetic space of PD. By studying the molecular mechanisms underlying familial PD, I will also gain novel insights into the etiology of sporadic PD.If successful, this project will deliver three important results: 1. I will obtain innovative therapeutic targets to modify disease progression. 2. I will reveal how protein homeostasis maintains synaptic function and 3. answer why this process is affected early in PD.