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A deep cellular atlas of the human ventral substantia nigra in Parkinson's identifies a genetic and molecular overlap with Type 2 Diabetes

Volpato, V.; Menassa, D.; Sheshadri, P.; Giussani, S.; Rokicki, M.; Cardo, L. F.; Bafaloukou, M.; Schalkamp, A.-K.; Zaremba, A.; Monzon-Sandoval, J.; Vinh, N.-N.; Morgan, J.; Hu, M. T. M.; Miners, S.; Wade-Martins, R.; Sandor, C.; Parkkinen, L.; Webber, C.

2025-05-28 neurology
10.1101/2025.05.28.25328401 medRxiv
Show abstract

Parkinsons disease (PD) is a complex neurodegenerative disorder characterised by selective neuronal loss. We integrate deep full-length single-nuclei sequencing of the human substantia nigra with novel genome-wide association studies (GWAS) identifying genetic and cellular drivers of PD. Genetic risk converges on AGTR1+ dopaminergic neurons and perineuronal oligodendrocytes (pODCs), both reduced in PD, as well as oligodendrocyte precursor cells, enriched among disease-disrupted intercellular interactions. AGTR1+ neurons represent a metabolically stressed state, characterised by renin-angiotensin system (RAS) and MAPK activation, oxidative stress, and mitochondrial dysfunction, rather than a distinct subtype. AGTR1+ neurons and pODCs link PD risk to metabolic traits; in pODCs, this association reflects insulin resistance with downregulated PI3K-AKT signalling. GWAS of comorbid PD and type 2 diabetes (T2D) identifies loci in AGTR1 and TCF7L2, while AGTR1+ neurons specifically upregulate RAS and T2D drug targets. Familial PD genes associated to comorbid PD/T2D associate with non-Lewy body PD, stratifying disease mechanisms.

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