Determinants of seeding and spreading of ?-synuclein pathology in the brain.

ABSTRACT: In Parkinson's disease (PD), fibrillar forms of ?-synuclein are hypothesized to propagate through synaptically coupled networks, causing Lewy pathology (LP) and neurodegeneration. To more rigorously characterize the determinants of spreading, preformed ?-synuclein fibrils were injected into the mouse pedunculopontine nucleus (PPN), a brain region that manifests LP in PD patients and the distribution of developing ?-synuclein pathology compared to that ascertained by anterograde and retrograde connectomic mapping. Within the PPN, ?-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 ?-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 ?-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.

SUBMITTER: Henrich MT 

PROVIDER: S-EPMC7673735 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature