Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.

Mitochondrial and lysosomal dysfunction are central features of Parkinson's disease (PD) across major genetic forms including PRKN, SNCA, and LRRK2. We applied cell morphomics, a machine-learning-based framework combining high-content imaging with quantitative feature extraction, to analyse mitochondrial and lysosomal morphology at single-cell resolution in iPS cell-derived cortical neurons from PD patients and healthy controls (13 lines total). Supervised machine-learning models distinguished PD neurons from controls with high accuracy (AUC = 0.87) and reliably separated individual genotypes. Feature importance and attribution analysis revealed genotype-specific organelle biases in the relative contribution of mitochondrial and lysosomal features, with mitochondrial features dominating classification in PRKN neurons, balanced mitochondrial and lysosomal contributions in SNCA neurons, and a greater lysosomal contribution in LRRK2 neurons. Multi-class models retained strong performance, and findings were reproduced across two independent laboratories using different dyes and imaging conditions. These results demonstrate that morphomics provides a robust and scalable framework to quantify genotype-specific organelle abnormalities in PD neurons and supports its application for cellular stratification and biomarker discovery.