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. Our study attempts to address this question by deploying a modeling framework to recreate the connectome-based model of synucleinopathy spread and probe the intersection of intrinsic cellular vulnerability of monoaminergic neurons and network-based spread.’Nexopathy in silico’ (NexIS) along with the MISS algorithm for spatial gene expression mapping serve as the model of choice that served as framework to understand 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. • We use cell-type distribution maps and directional spread weighting to model α -synuclein pathology spread in mouse models; these two factors synergistically created the best recapitulation of empirical pathology. • Hindbrain Noradrenergic and Midbrain Dopaminergic neurons are the strongest cell-type mediators of network-wide spread. • Noradrenergic cell types provide the most informative signal for late-stage (12-month) pathology and can outperform regional α -synuclein expression as a predictor of long-term burden. • Noradrenergic and Dopaminergic neuronal types resulted in models with distinctly different fitted parameters for intra and inter-regional accumulation and transmission patterns.