Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease

• Published in: The Journal of experimental medicine Vol. 213; no. 9; pp. 1759 - 1778
• Main Authors: Rey, Nolwen L, Steiner, Jennifer A, Maroof, Nazia, Luk, Kelvin C, Madaj, Zachary, Trojanowski, John Q, Lee, Virginia M-Y, Brundin, Patrik
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 22-08-2016; The Rockefeller University Press
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Animals; Disease Models, Animal; Disease Progression; Female; Lewy Bodies - pathology; Life Sciences; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons and Cognition; Olfactory Bulb - metabolism; Olfactory Tubercle - metabolism; Parkinson Disease - etiology; Protein Aggregation, Pathological - etiology; Protein Aggregation, Pathological - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20160368

Parkinson's disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded α-synuclein (α-syn). The aggregates are believed to propagate via neural pathways following a stereotypical pattern, starting in the olfactory bulb (OB) and gut. We hypothesized that injection of fibrillar α-syn into the OB of wild-type mice would recreate the sequential progression of Lewy-like pathology, while triggering olfactory deficits. We demonstrate that injected α-syn fibrils recruit endogenous α-syn into pathological aggregates that spread transneuronally over several months, initially in the olfactory network and later in distant brain regions. The seeded inclusions contain posttranslationally modified α-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading α-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating α-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD.