Selective vulnerability of monoaminergic neurons and network spread of alpha-synuclein jointly explain pathology progression in Parkinson's disease models.

The trans-synaptic propagation of α-synuclein aggregates is a defining feature of Parkinson's disease, yet how specific cellular phenotypes interact with the brain's structural connectome to govern disease progression remains a fundamental question in neurobiology. Here, we address this question using a connectome-based modeling framework that simulates synucinopathy spread along the mouse structural connectome, to examine how monoaminergic cell-type vulnerability and network-based transmission jointly shape pathology progression. 'Nexopathy in silico' (NexIS), along with the MISS algorithm for spatial gene expression mapping, provided a framework to examine how regional and cellular context impact synucleinopathy spread. In particular we focus on monoaminergic neurons, since inadequate clearance of pathologic α-synuclein species in monoaminergic neurons is a prominent hypothesis implicated in PD. We delineate the specific roles of monoaminergic cell types and directional transmission of α-synuclein arising from axonal transport polarity in shaping α-synuclein pathology in mouse models. Our analysis reveals that hindbrain noradrenergic (HBNOR) and midbrain dopaminergic (MBDOP) cell-type distributions are the primary mediators of network-wide transmission, with the former outperforming endogenous regional Snca expression as predictors of long-term pathology. Crucially, we demonstrate a synergistic effect between cell-type vulnerability and retrograde-biased transport, finding that both factors are required to accurately recapitulate empirical spatiotemporal patterns at 6 and 12 months post-seeding. This work constitutes one of the most mechanistically complete models of synucleinopathy to date, providing a comprehensive theoretical bridge that links microscale molecular motor regulation to macroscale regional vulnerability. Our findings suggest that the interaction between noradrenergic cell-type distribution and retrograde transport serves as the dominant driver of late-stage progression, offering highly specific cellular and mechanistic targets for therapeutic intervention.