title: Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease.
abstract: 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.
authors: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503 Nolwen.Rey@vai.org.
authors: Nolwen L
authors: NL
authors: Rey
authors: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503.
authors: Jennifer A
authors: 0000-0003-0953-1310
authors: JA
authors: Steiner
authors: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503 Roche Pharma Research & Early Development, Neuroscience Discovery, Roche Innovation Center, 4070 Basel, Switzerland.
authors: Nazia
authors: 0000-0002-9611-041X
authors: N
authors: Maroof
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104.
authors: Kelvin C
authors: 0000-0002-6591-6269
authors: KC
authors: Luk
authors: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503.
authors: Zachary
authors: 0000-0003-2330-0500
authors: Z
authors: Madaj
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104.
authors: John Q
authors: 0000-0002-9239-8794
authors: JQ
authors: Trojanowski
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104.
authors: Virginia M-Y
authors: VM
authors: Lee
authors: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503.
authors: Patrik
authors: 0000-0003-2924-5186
authors: P
authors: Brundin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016631:Lewy Bodies / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways; D009830:Olfactory Bulb / Q000378:metabolism*; D066208:Olfactory Tubercle / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology*; D066263:Protein Aggregation, Pathological / Q000209:etiology / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein