Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD and SNCA dosage has been linked to the severity of PD4,5. For other PD-associated variants, e.g., GBA and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been associated with mitochondrial (dys)function and/or protein degradation pathways6–8. On the other hand, transcriptomic changes between PD patients and non-neurological controls of selected brain regions, e.g., the substantia nigra, have identified several molecular mechanisms underlying PD pathology, including synaptic vesicle endocytosis9–11. However, post-mortem human brain tissue of well-characterized PD patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited coverage of patients with different Braak LB stages, resulting in low concordance of findings across different studies12.
