Identifying mechanisms of dopaminergic neuron resilience and their roles in Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor deficits such as tremor, muscle stiffness, and slowness of movement, and affects 6 million worldwide. Despite ongoing efforts to discover the mechanisms underlying this disease, PD remains an incurable disorder. Major challenges include tremendous heterogeneity in disease progression and severity, as well as a lack of reliable, scalable in vitro models to find new therapeutic targets. Though most PD cases have no known genetic cause, those that do (e.g. GBA, LRRK2, or SNCA) exhibit pathologies common to most patients, including a-synuclein aggregates (Lewy bodies), and defective lysosomal/mitochondrial function. Here, this research project proposes to (1) develop and carefully characterize scalable iPS-derived dopaminergic (iDA) neurons treated with pre-formed a-synuclein fibrils (PFFs). PFF treatment induces Lewy body formation, closely modeling native PD neurons. The team will quantify cell viability, as well as the composition and health of lysosomes and mitochondria. They will then (2) conduct unbiased CRISPR screens to identify regulators of neuronal resilience in the presence of PFF, focused on several key PD features. This study will identify essential factors controlling disease progression and establish a critically needed experimental system to develop therapies that could reverse dopaminergic neuron cell death.