Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease
Arlin Keo, Ahmed Mahfouz, Angela Ingrassia, Jean-Pascal Meneboo, Céline Villenet, Eugénie Mutez, Thomas Comptdaer, Boudewijn P. F. Lelieveldt, Martin Figeac, Marie‐Christine Chartier‐Harlin, Wilma D. J. van de Berg, Jacobus J. van Hilten, Marcel Reinders
Abstract
The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of non-neurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.