With this, I would like to thank the CIHR, Croucher Foundation, Parkinson Canada @parkinsoncanada.bsky.social , Peterborough KM Hunter Charitable Foundation, and Ontario Graduate Scholarship for funding our research.
If you've read this far, thank you for reading and I'm happy to take any questions!

Our findings also imply that even when experimental conditions are all controlled for, strain variability inherently exists in de novo α-syn aggregates generated in vitro or derived from the M83 mouse model. This needs to be taken into account when we design/interpret α-syn studies in the future.

Our observations that distinct strains come from the same experimental setup (for recombinant α-syn) and from the same genotype of mice (for naturally occurring aggregates) suggest that random protein misfolding is a major driver of α-syn strains and disease heterogeneity in the synucleinopathies.

As homozygous M83 mice spontaneously develop synucleinopathies, we also examined the naturally occurring strain diversity of their α-syn aggregates, and found that they could form 1 of 3 types of aggregates, which propagated as 3 different strains.

i.e. Multiple strains arise naturally, randomly.

Using biochemical assays and cryo-EM, we found that in the same condition, wild-type and A53T-mutant α-syn can form multiple α-syn structures. These structures propagated as distinct strains in our mouse model (M83 mice, which overexpresses the A53T-mutant human α-syn and develops a fatal disease)

With the link between different strains and different diseases established, we then wondered why different strains form. Specifically, we asked whether different strains can form when aggregates are made in identical conditions -- because if so, the reason may be random misfolding.

Spoiler: yes.

That shape/structure is what we call a "conformational strain." Previously, we published that making α-syn aggregates in the test tube in the presence vs. absence of salt creates two different strains that cause drastically different neurological diseases in mice www.nature.com/articles/s41...

Weirdly enough, a vast majority of Parkinson's and DLB patients, and all MSA patients, express the same wild-type version of α-syn. So why do different patients get different diseases? The secret may lie in the shape in which multiple α-syn proteins are attached www.sciencedirect.com/science/arti...

Alpha-synuclein protein aggregates are a common pathological hallmark of multiple neurodegenerative diseases, including Parkinson's, Multiple System Atrophy, and Dementia with Lewy Bodies. α-Syn gene duplications, triplications, and mutations are known causes for familial Parkinson's and DLB.