Unraveling the role of alpha-synuclein strains in synucleinopathies

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 clinicopathological traits observed in patients. Understanding the exact role of αSYN in the etiopathogenesis of synucleinopathies and how one single protein may account for the development of these distinct diseases remains a tremendous challenge. 

The recent discovery that αSYN assembles into structurally and functionally distinct fibrillar polymorphs has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneity within synucleinopathies. A parallel comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies, aiming to reveal the existence and relevance of distinct αSYN strains in the human brain, is missing so far. Hence, we addressed the structural-functional relationship of αSYN aggregates directly derived from the brain of patients with PD, MSA and DLB. We show that total brain homogenates and in vitro amplified fibrillar αSYN assemblies possess distinct structural traits and drive neuropathology in vivo, reflecting the characteristics of synucleinopathies in patients.

Although protein aggregation appears to govern synucleinopathy progression, this does not entirely capture the complexity of the disease mechanisms. The role of inflammatory processes within this intricate context, for example, has not been yet disentangled. Extracellular transmission of distinct αSYN strains could impact the immune tolerance and subsequent reaction, affecting neuronal integrity through the release of pro-inflammatory cytokines. Here, we explored the immunological properties of distinct recombinant and patient-derived αSYN strains and demonstrate that recombinant fibrillar αSYN assemblies are more potent than monomeric and oligomeric species in inducing microglial activation. We furthermore show that patient-derived αSYN strains trigger a differential immune response in vivo. These findings promote the idea that αSYN strains represent unique antigens, which might determine disease outcome. 

With this work, we provide new evidence that underlines the relevance of αSYN strains in synucleinopathies. The development of highly sensitive techniques with the aim of detecting pathological αSYN strains might contribute to earlier and specific diagnosis of synucleinopathies. Therapeutic strategies specifically targeting disease-specific strains or their unique interactome might open new avenues aimed at slowing or stopping disease progression.