Project
Unraveling cell-type-specific disease modifier pathways in familial Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenerative disorder with only symptomatic treatments but no cures. PD hallmarks are hypokinesia, rigidity, and tremor resulting from dopaminergic cell loss. In addition, PD is characterized by several non-motor symptoms which indicate that also other cell types significantly contribute. Yet we do not have a comprehensive overview of all cell types relevant to PD and the underlying pathways. To study this question in an unbiased and brain-wide manner, my host laboratory performed single-cell RNA sequencing across entire fly brains of Drosophila PD models and revealed >10 cell types that are highly transcriptionally deregulated, even at an early time point prior to dopaminergic impairment. This project will build on these results and aims to relate this ‘transcriptional vulnerability’ to neuronal function to learn from these cell-type specific transcriptional responses on how to improve cellular health. I will assess neuronal excitability and synaptic vesicle cycling by means of sensitive live imaging in transcriptionally deregulated cell types. I will also assess cell-type specific neurodegeneration by means of automated neuronal counting and test whether further genetically up-/downregulating deregulated genes within these cell types is improving cellular function. Collectively, these experiments will yield novel cell types underlying PD and suggest new cell type specific disease modifiers that will be assessed in the future in human system.