Pathogenesis of α-synuclein strains in disease.

Amanda Woerman

Synucleinopathies, including multiple system atrophy (MSA) and the Lewy body diseases (LBDs) – Parkinson’s disease, Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies – are caused by misfolding of the protein a-synuclein into multiple conformations, or strains. Experimental data investigating these two strain types demonstrate distinct biological and structural differences between MSA and LBDs, including the ability of MSA patient samples to readily transmit neurological disease to TgM83^+/- mice, which express human a-synuclein with the A53T mutation, following intracranial (i.c.) inoculation. By comparison, i.c. inoculation using LBD patient samples has only been shown to induce pathology in the absence of clinical disease. Unexpectedly, we recently identified one PDD human patient sample that induced neurological signs following i.c. inoculation with an incomplete attack rate over an extended incubation period. Intriguingly, the tissue sample used to generate our inoculum, the substantia nigra, contained Lewy bodies as well as glial cytoplasmic inclusions, suggesting the patient had both PDD and MSA. Hypothesizing that the prolonged incubation period was a result of low titer MSA present in the patient sample, we performed secondary passage using two of the terminal mouse samples. While both samples transmitted disease with a shortened incubation period, consistent with increased titer, subsequent analysis of frozen tissue from secondary passage using our panel of mutant a-syn140-YFP biosensor cells showed the strain isolated from passaging the PDD human patient sample has unique biological properties compared to the a-synuclein strain(s) present in MSA patient samples. These data provide evidence for the isolation of a distinct a-synuclein strain and raise important questions about the clinical consequences arising from the interaction between two a-synuclein strains in a single human patient.