The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies

International audience ; Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein ($\alpha$SYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar $\alpha$SYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different $\alpha$SYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct $\alpha$SYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of $\alpha$SYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of $\alpha$SYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human $\alpha$SYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified $\alpha$SYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of $\alpha$SYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, $\alpha$SYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.