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

TLDR

Synucleinopathies such as Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies are marked by α‑synuclein aggregates that differ in clinical and pathological features, and recent work on pure fibrillar α‑synuclein polymorphs suggests that distinct strains may drive this heterogeneity. The study aims to characterize distinct α‑synuclein strains in human brains and link their structures to disease pathology. Brain‑derived α‑synuclein aggregates from PD, MSA, and DLB patients were used to seed monomeric human α‑synuclein in vitro via protein misfolding cyclic amplification, generating strain‑specific fibrils for analysis. The intrinsic structure of the amplified fibrils determines disease characteristics, with MSA strains being more potent than PD strains in inducing motor deficits, neurodegeneration, pathology, spreading, and inflammation, while DLB strains show minimal effects, establishing distinct signatures for each synucleinopathy.

Abstract

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 (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN 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, αSYN 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.