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

Martin T. Henrich, Fanni F. Geibl, Harini Lakshminarasimhan, Anna Stegmann, Benoit I. Giasson, Xiaobo Mao, Valina L. Dawson, Ted M. Dawson, Wolfgang H. Oertel, D. James Surmeier

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbereabc2487
JournalScience Advances
Volume6
Issue number46
DOIs
StatePublished - Nov 11 2020

ASJC Scopus subject areas

  • General

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