TESTING THE BRAAK HYPOTHESIS BY INVESTIGATING THE MOLECULAR MECHANISMS BY WHICH ALPHA-SYNUCLEIN AGGREGATES CAN BE TRANSPORTED ALONG THE VAGAL SENSORY NEURONS AND WHAT MODULATES THIS TRANSPORT
Embargo until
2027-08-01
Date
2023-06-16
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Johns Hopkins University
Abstract
Lewy bodies composed by alpha-synuclein (α-syn) aggregates may be found in the gut of PD patients before they present in the brain, consistent with Braak’s hypothesis of centripetal transmission of Parkinson’s disease (PD). It was recently shown that trans neuronal propagation of pathologic a-synuclein from the gut to the brain can result in PD in mice. However, the neuronal pathways from the gut to the CNS have yet to be fully understood. Although it is widely believed that vagal motor neurons are involved, sensory fibers are more logical candidates for such transport. We therefore hypothesized that pathological α-syn aggregates originating in the gut are taken up by the vagus sensory nerve terminals in the gut and transported by specific motor proteins in the vagus sensory nerve to the brain. Our aim was to study the axonal transport of α-syn aggregates along the vagal sensory neurons. In our study, a successful in vitro model of the polarized vagal sensory neurons was established. In this model, the cultured vagal sensory neurons were able to take up and transport α-syn preformed fibrils (PFF) without exhibiting overt toxicity. In addition, fluorescently tagged PFF injected in the gut of the mice were observed in the vagal sensory ganglia (nodose) 5 weeks post injection, which evidenced the role of the vagal sensory neurons in transportation of α-syn. Two molecular motors, kinesin, and dynein were identified via immunoprecipitation for transporting α-syn aggregates along the vagus nerve. Electrical stimulation sped up the transportation of α-syn aggregates along the cultured vagal sensory neurons, revealing the activity-dependent nature of α-syn transportation. This study contributed significantly to understanding the gut-centric PD pathogenesis and paved the way for developing novel therapeutics to prevent the progression of the gut-centric PD.
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Keywords
Parkinson's Disease
Alpha-Synuclein
Axonal Transport
Vagus Nerve
Nodose Neurons
Braak Hypothesis