Abstract
In synucleinopathies, the protein α-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. We recently reported the unexpected finding of a novel α-synuclein strain in a Parkinson’s disease with dementia patient sample containing GCI-like co-pathology along with widespread LB pathology, which led us to question if two α-synuclein strains can interact with one another in a patient and, if so, can strain competition occur. To test this possibility, we used the strain interference 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 α-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. We found that the two α-synuclein strains exhibited a synergistic effect during neuroinvasion, which was characterized by a decrease in incubation period along with evidence of the mouse-passaged MSA strain in the brain of terminal animals. These findings indicate that two α-synuclein strains can synergize with one another to accelerate the progression of clinical disease, representing a novel outcome in mixed infection studies.