Parkinson’s disease (PD) is a complex neurodegenerative disorder marked by selective neuronal loss. Here, we integrate deep, full-length single-nuclei sequencing of the human substantia nigra across PD stages with genome-wide association studies to uncover genetic and cellular interactions driving neurodegeneration. We find that PD genetic risk converges in AGTR1+ dopaminergic neurons and perineuronal satellite oligodendrocytes (psODCs), both reduced in PD, alongside oligodendrocyte precursor cells (OPCs) that exhibit altered isoform usage within OPC-psODCs differentiation. These cell subtypes form a genetic risk-enriched network of interactions, lost early in disease progression. We identify AGTR1+ neurons as a metabolically stressed state, not a distinct cell type, exhibiting renin-angiotensin system (RAS) and MAPK activation, oxidative stress, and mitochondrial dysfunction. A GWAS of coincident PD and type 2 diabetes (T2D) identifies significant loci in AGTR1 and TCF7L2, establishing a mechanistic explanation for their comorbidity, while AGTR1+ neurons appear directly targeted by RAS and T2D therapeutics providing the missing mechanistic explanation for their repurposing to PD.
SPEAKER BIOGRAPHY
After obtaining his PhD from the European Bioinformatics Institute and Cambridge University, Caleb joined Oxford University contributing to almost all of the major large-scale genome projects. The group he established in Oxford in 2011 gained insights into complex neurological disorders using functional, integrative and network genomics, combined with statistical genetics and iPSC modelling. In 2018, he joined the UK Dementia Research Institute where his programme generates and interprets large-scale molecular data sets from human tissue in order to identify genes and processes that contribute to many complex neurodegenerative disorders, and then validates findings within iPSC models. Within the UK-DRI, he was appointed as the national Director of Informatics with a mission to democratise and integrate data to empower researchers within the UK Dementia Research Institute and beyond.
