Khedmatgozar, C. R. | Search bioRxiv

bioRxiv2026

Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice

Synucleinopathies are a group of neurodegenerative diseases characterized by the presence of misfolded -synuclein inclusions which cause progressive disease by spreading throughout the brain in a prion-like manner. Throughout the neurodegenerative disease field, the ability of a single protein to give rise to multiple distinct clinical disorders is explained by the strain hypothesis, or the idea that the misfolded protein conformation determines the resulting disease. This was initially shown using transmission studies in cell lines and mouse models; more recently cryo-electron microscopy (cryo-EM) validated this idea by identifying distinct -synuclein filament folds in brain tissues from patients with Parkinsons disease, multiple system atrophy (MSA), and juvenile-onset synucleinopathy. However, very little is known about the -synuclein filament structures that form in animal models of these disorders, and thus their relevance to human disease and suitability as models for therapeutic development remains a question. Here we report the first atomic resolution cryo-EM structures of -synuclein fibrils from an MSA patient sample before and after transmission to a transgenic mouse model of disease. Our findings indicate that while distinct adaptations occur during fibril replication in the mouse host, key structural facets are maintained, validating the merits of this transmission model for supporting preclinical research on MSA.

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bioRxiv2025

Co-infection with two α-synuclein strains reveals novel synergistic interactions

In synucleinopathies, the protein -synuclein misfolds into Lewy bodies (LBs) in patients with Lewy body disease (LBD) or into glial cytoplasmic inclusions (GCIs) in patients with multiple system atrophy (MSA). The ability of a single misfolded protein to cause disparate diseases is explained by the prion strain hypothesis, which argues that protein conformation is a major determinant of disease. While structural, biochemical, and biological studies show that LBD and MSA patient samples contain distinct -synuclein strains, we recently reported the unexpected finding of a novel -synuclein strain in a Parkinsons disease with dementia patient sample containing GCI-like co-pathology along with widespread LB pathology. This finding led us to question if two -synuclein strains can interact with one another in a patient and, if so, can strain competition occur. Notably, this would not only impact the clinical presentation of disease but would also have profound impacts on successful therapeutic development. To test this possibility, we used the strain interference superinfection model developed in the prion field, in which a slower replicating strain--in this study, mouse-passaged MSA--is used to compete with a faster replicating strain--here, recombinant preformed fibrils (PFFs)-- following sciatic nerve (sc.n.) inoculation. Unexpectedly, we found that PFFs generated using the same method differed in their ability to neuroinvade following sc.n. inoculation based on -synuclein monomer source. Using a PFF preparation that does spread from the periphery, we conducted strain competition studies by first injecting TgM83+/- mice with mouse-passaged MSA into the sc.n. followed by a second injection with PFFs at 30, 45, and 60% of the MSA incubation period. Unlike in the prion field, where the faster replicating strain inhibits the slower strain at the 30 and 45% time points, we found that the two -synuclein strains exhibited a synergistic effect during neuroinvasion. Notably, disease onset across the three cohorts was shortened compared to MSA inoculation alone, and brains from terminal animals showed evidence of both the PFF and mouse-passaged MSA strains, suggesting the two strains worked together to accelerate neuroinvasion in the mice. These findings have important implications for disease progression in patients with -synuclein co-pathologies. The finding that two strains can synergize with one another to accelerate the progression of clinical disease represents a novel outcome in mixed infection studies and more broadly expands our understanding of the effect of prion strain biology on disease pathogenesis.

neuroscience↗