PT - JOURNAL ARTICLE AU - Henrich, Martin T. AU - Geibl, Fanni F. AU - Lakshminarasimhan, Harini AU - Stegmann, Anna AU - Giasson, Benoit I. AU - Mao, Xiaobo AU - Dawson, Valina L. AU - Dawson, Ted M. AU - Oertel, Wolfgang H. AU - Surmeier, D. James TI - Determinants of seeding and spreading of α-synuclein pathology in the brain AID - 10.1126/sciadv.abc2487 DP - 2020 Nov 01 TA - Science Advances PG - eabc2487 VI - 6 IP - 46 4099 - http://advances.sciencemag.org/content/6/46/eabc2487.short 4100 - http://advances.sciencemag.org/content/6/46/eabc2487.full SO - Sci Adv2020 Nov 01; 6 AB - 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.