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Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment
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Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment
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Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment
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Journal Article
Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment
2018
Overview
Accumulating evidence suggests that the lesions of Parkinson’s disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5–10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo
.
Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit–dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state.
Publisher
BioMed Central,BioMed Central Ltd,BMC
Subject
/ alpha-Synuclein - metabolism
/ Animals
/ Biomedical and Life Sciences
/ Botulinum Toxins, Type A - metabolism
/ Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism
/ Humans
/ NAV1.2 Voltage-Gated Sodium Channel - metabolism
/ Neurons
/ Parkinson Disease - pathology
/ Seeds
/ Synaptic Vesicles - drug effects
