AbstractParkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) are neurodegenerative disorders with alpha‐synuclein (α‐syn) aggregation pathology. Different strains of α‐syn with unique properties are suggested to cause distinct clinical and pathological manifestations resulting in PD, MSA, or DLB. To study individual α‐syn spreading patterns, we injected α‐syn fibrils amplified from brain homogenates of two MSA patients and two PD patients into the brains of C57BI6/J mice. Antibody staining against pS129‐α‐syn showed that α‐syn fibrils amplified from the brain homogenates of the four different patients caused different levels of α‐syn spreading. The strongest α‐syn pathology was triggered by α‐syn fibrils of one of the two MSA patients, followed by comparable pS129‐α‐syn induction by the second MSA and one PD patient material. Histological analysis using an antibody against Iba1 further showed that the formation of pS129‐α‐syn is associated with increased microglia activation. In contrast, no differences in dopaminergic neuron numbers or co‐localization of α‐syn in oligodendrocytes were observed between the different groups. Our data support the spreading of α‐syn pathology in MSA, while at the same time pointing to spreading heterogeneity between different patients potentially driven by individual patient immanent factors.

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