Propagation of α-synuclein pathology: models, mechanisms and future goals.

Misfolding and aggregation of α-synuclein underlies several progressive neurodegenerative disorders for which there are no disease-modifying therapies, most notably Parkinson's disease. α-Synuclein pathology can be transmitted across adjacent cells, and this prion-like property is thought to underlie disease progression. Here, we review what is known about how α-synuclein pathology spreads between cells and evaluate the different model systems used to address this question, including cultured cells, invertebrates, rodents, and non-human primates. Cellular systems have revealed potential molecular mechanisms underlying α-synuclein release and uptake. However, they lack the physiological complexity needed to recapitulate circuit-level spread. Invertebrate models overcome this limitation but lack endogenous α-synuclein. Rodents are the most frequently used model and have provided key insights into the anatomical progression of pathology. Inoculation of pathogenic α-synuclein into targeted regions initiates sequential involvement of connected structures, revealing principles such as directionality, selective vulnerability, and synaptic connectivity to pathology propagation. Yet, they incompletely model the slow time course and multisystem involvement seen in patients. Non-human primate models offer a closer representation of human neuroanatomy, synaptic organization, and lifespan. These models capture features such as long-distance propagation, dopaminergic neuron degeneration, and the emergence of motor symptoms over extended periods. Their value lies in bridging molecular mechanisms with organism-level dysfunction, but they face technical and practical limitations. Together, these complementary systems have provided insight into how α-synuclein pathology spreads across the brain. In reviewing the literature, we find there is little consensus and no cogent understanding of the mechanisms underlying release and uptake of pathologic α-synuclein aggregates. We propose a need for a deeper understanding of how α-synuclein aggregation spreads. This requires integrating insights across cellular, rodent, and primate models and leveraging the strengths of each system to enable the identification of targetable mechanisms of transmission and guide the development of disease-modifying therapies.