Determinants of seeding and spreading of α-synuclein pathology in the brain

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Abstract

In Parkinson's disease (PD), fibrillar forms of α-synuclein are hypothesized to propagate through synaptically coupled networks, causing Lewy pathology (LP) and neurodegeneration. To more rigorously characterize the determinants of spreading, preformed α-synuclein fibrils were injected into the mouse pedunculopontine nucleus (PPN), a brain region that manifests LP in PD patients and the distribution of developing α-synuclein pathology compared to that ascertained by anterograde and retrograde connectomic mapping. Within the PPN, α-synuclein pathology was cell-specific, being robust in PD-vulnerable cholinergic neurons but not in neighboring noncholinergic neurons. While nearly all neurons projecting to PPN cholinergics manifested α-synuclein pathology, the kinetics, magnitude, and persistence of the propagated pathology were unrelated to the strength of those connections. Thus, neuronal phenotype governs the somatodendritic uptake of pathological α-synuclein, and while the afferent connectome restricts the subsequent spreading of pathology, its magnitude and persistence is not a strict function of the strength of coupling.

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Henrich, M. T., Geibl, F. F., Lakshminarasimhan, H., Stegmann, A., Giasson, B. I., Mao, X., … Surmeier, D. J. (2020). Determinants of seeding and spreading of α-synuclein pathology in the brain. Science Advances, 6(46). https://doi.org/10.1126/sciadv.abc2487

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