α-Synuclein pathology spread through the brain connectome is modulated by selective vulnerability and predicted by network analysis

Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically-connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, factors regulating spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here, we use quantitative pathology mapping in the mouse brain combined with network modeling to understand the spatiotemporal pattern of spread. α-Synuclein pathology patterns are well-described by a network model based on two factors—anatomical connectivity and endogenous α-Synuclein expression. The map and model allow assessment of selective vulnerability to α-Synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor impacts the spread and toxicity of α-Synuclein pathology.