Multiple studies suggests that a cytotoxic role and prion-like transfer of α-synuclein may contribute to its progressive spread across the brain in PD, assuming a gain-of-function3,27,28. In line with this assumption are reports of familial PD caused by SNCA multiplications, suggesting a SNCA dosage effect in causing PD4,5. Interestingly, in contrast to the temporal and spatial pattern of the α-synuclein distribution associated with the ascending Braak scheme in PD, the SNCA expression signature across brain regions R1–R6 in non-neurological brains followed a reverse pattern with lowest expression in preclinically involved regions (brainstem) and highest expression in clinically involved regions (limbic system and cortex). Expression changes between regions were larger in PD and iLBD brains, because of lower expression in preclinically involved regions compared to age-matched controls. The abundance of physiological SNCA in non-neurological brains suggests a protective role, while at the same time it may impact vulnerability to LB pathology in PD brains as demonstrated in earlier studies detecting both proteins and mRNA levels (literature overview in Supplementary Table 4). Cell lines or animal models without SNCA showed a synaptic
