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.