The Stratification of Sporadic Parkinson’s Disease Patients by Cellular Mechanism.

Parkinson’s Disease (PD) is an incurable neurodegenerative disease that is widely recognised to be heterogeneous both mechanistically and clinically. Several dysfunctional mechanisms have been identified, including mitochondrial and lysosomal dysfunction. Disease-modifying therapeutics target specific mechanisms of disease to repair dysfunction. A key reason why neuroprotection trials have failed in PD is that clinical trials select participants without considering mechanism heterogeneity.
We investigated mitochondrial and lysosomal dysfunction in patient-derived fibroblasts from a new cohort of sporadic PD patients and healthy controls; these two key mechanisms are promising targets for therapeutics. Imaging and biochemical assays assessed organelle health and mitochondrial and lysosomal dysfunction scores were generated for each cell line. The patients were stratified by identifying distinct patterns of dysfunction within their cells. Further investigation of mitochondria and lysosome function was conducted in the subgroup’s fibroblasts to validate stratification. Some fibroblast lines from the subgroups were reprogrammed into induced neuronal progenitor cells and differentiated into induced dopaminergic neurons to identify defining mechanisms of dysfunction in a disease-relevant cell type.
85 % of the organelle health parameters showed significantly more variation in the patient population, demonstrating mechanism heterogeneity. Stratification identified four distinct subgroups defined by either mitochondrial dysfunction, lysosomal dysfunction or a combination of dysfunction in both organelles. Further investigation of the lysosomal dysfunction subgroup showed a reduction in Cathepsin D activity in the fibroblasts and significant enlargement of lysosomes in induced dopaminergic neurons. A lack of oxidative phosphorylation flexibility was observed in the fibroblasts from the mitochondrial dysfunction subgroup and elevated complex V activity was observed in one of the mixed dysfunction subgroups. This study outlines a new method of stratification that can produce more homogeneous groups of PD patients. This method could be used to improve clinical trial design, identify new biomarkers and discover new mechanisms to target mechanistically.