Cologne Seminars on Ageing "Insights into the Mitochondrial Biology of Parkinson’s Disease from Large Scale Patient Cohorts to in Depth Studies on iPSC-derived Dopaminergic Neurons"

About Dr. Fitzgerald's talk:

Mitochondrial dysfunction is a central feature of Parkinson’s disease, linking genetic and environmental factors. Our studies of donated human biofluids reveal clear signatures of mitochondrial damage in patients and in individuals at risk. Somatic mitochondrial DNA (mtDNA) changes reflect early disease processes associated with conversion and clinical manifestation. In the central nervous system, mtDNA copy number normally expands with age, but this adaptive response appears restricted to healthy individuals and is absent in Parkinson’s disease. Our findings suggest that lifelong trajectories of mitochondrial damage, and the capacity to compensate, shape early disease biology independently of synuclein burden. We have developed assays to show that defective mitophagy can also be detected during prodromal PD.

What mechanisms drive such mitochondrial changes in the periphery and CNS? We study mitochondria outside cells and those packaged into extracellular vesicles. To investigate mitochondrial dysfunction in disease-relevant cell types, we use induced pluripotent stem cells from Parkinson’s patients and healthy controls combined with allele-specific gene editing to generate isogenic lines. These are differentiated into dopaminergic neurons and glia to model early disease stages. Our work reveals a metabolic shift caused by PINK1 loss of function that alters synaptic composition and dopaminergic neurotransmission. Genome-wide screening further identified gene dependencies enabling Parkinson’s disease cells to bypass autophagy under low nutrient conditions.

This event is aimed at a specialist audience.