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, the factors regulating the 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. Patterns of α-synuclein pathology are well described by a network model that is based on two factors: anatomical connectivity and endogenous α-synuclein expression. The map and model allow the 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 affects the spread and toxicity of α-synuclein pathology.
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The authors thank members of the laboratory for their feedback in developing this manuscript. This study was supported by the Michael J. Fox Foundation (9530.01 to M.X.H and V.M.Y.L.) and the following NIH grants: T32-AG000255 (to M.X.H. and V.M.Y.L.), P30-AG010124 (to J.Q.T.) and P50-NS053488 (to V.M.Y.L.). D.S.B. also acknowledges support from the John D. and Catherine T. MacArthur Foundation, the ISI Foundation, the Alfred P. Sloan Foundation, the Paul G. Allen Foundation, the National Institute of Neurological Disorders and Stroke (R01 NS099348), and the National Science Foundation (BCS-1441502, BCS-1430087, NSF PHY-1554488 and BCS-1631550).
The authors declare no competing interests.
Peer review information: Nature Neuroscience thanks Ellen Kuhl, Tiago Outeiro, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Henderson, M.X., Cornblath, E.J., Darwich, A. et al. Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat Neurosci 22, 1248–1257 (2019). https://doi.org/10.1038/s41593-019-0457-5
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