Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 9, Pages 1759-1778Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160368
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Funding
- Van Andel Research Institute
- Peter C. and Emajean Cook Foundation
- Roche Postdoctoral Fellowship (RPF) grant
- European Research Council [PRISTINE-PD 269064]
- Michael J. Fox Foundation
- National Institutes of Health [NIA PO1 AG 17586-10, PO1 AG-032953, NINDS P50 NS053488-02, NIA UO1 AG029213-01]
- Cure Parkinson's Trust
- TEVA Neuroscience
- East Tennessee Foundation
- KiMe Fund
- Campbell Foundation
- Penn Morris K. Udall Parkinson's Disease Research Center of Excellence [NS53488]
- Marian S. Ware Alzheimer Program
- Renovo Neural, Inc.
- Roche
- Teva Inc
- Lundbeck A/S
- AbbVie
- ClearView Healthcare
- FCB Health
- IOS Press Partners
- Capital Technologies, Inc.
- Renovo
- Teva/Lundbeck
- Takeda Pharmaceutical Company Ltd.
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Parkinson's disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded alpha-synuclein (alpha-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 alpha-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 alpha-syn fibrils recruit endogenous alpha-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 post-translationally modified alpha-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading alpha-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating alpha-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD.
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