ArticleNeurobiology of disease2026
Selective vulnerability of monoaminergic neurons and network spread of alpha-synuclein jointly explain pathology progression in Parkinson's disease models.
Article in Neurobiology of disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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