Self-assembling synuclein induces controllable Parkinsonian pathology in vitro and in vivo

Many neurodegenerative diseases (NDs) feature abnormal protein aggregates in neurons. A notable example is the aggregation of a-synuclein (aSyn) in Parkinsons disease (PD). The mechanisms underlying the formation of these abnormal aggregates and their contribution to the pathogenesis of NDs remain unclear. Here we tackle this question from a build-to-understand perspective by recreating aSyn aggregates that recapitulate PD pathologies. We developed a novel system named self-assembling a-synuclein (SAS), which enables aSyn to form different types of aggregates within the cells. This allows us to rapidly screen for aggregates that induce Ser129 phosphorylation (pS129) of aSyn and neuronal axon retraction, which are key pathologies of PD. To further validate if the SAS-induced aggregates can fully recapture PD pathologies in vivo, SAS was delivered into mice non-invasively using the adeno-associated virus PHP.eB (AAV-PHP.eB). SAS-injected mice exhibited impaired motor function, loss of dopaminergic neurons and projections, and reduced dopamine levels. Furthermore, SAS-induced aSyn aggregates can propagate from dopaminergic neurons to other neurons. We demonstrated that this novel system can induce temporally controlled, tunable, and cell-type-specific PD pathology, with potential applicability to other NDs. This not only provides valuable tools to model and study PD quantitatively and repetitively but also offers new insights into the mechanisms of protein aggregation.