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| Journal Article | DZNE-2023-00310 |
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2023
MDPI
Basel
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Please use a persistent id in citations: doi:10.3390/cells12040569
Abstract: Neuron-to-neuron transfer of pathogenic α-synuclein species is a mechanism of likely relevance to Parkinson's disease development. Experimentally, interneuronal α-synuclein spreading from the low brainstem toward higher brain regions can be reproduced by the administration of AAV vectors encoding for α-synuclein into the mouse vagus nerve. The aim of this study was to determine whether α-synuclein's spreading ability is shared by other proteins. Given α-synuclein synaptic localization, experiments involved intravagal injections of AAVs encoding for other synaptic proteins, β-synuclein, VAMP2, or SNAP25. Administration of AAV-VAMP2 or AAV-SNAP25 caused robust transduction of either of the proteins in the dorsal medulla oblongata but was not followed by interneuronal VAMP2 or SNAP25 transfer and caudo-rostral spreading. In contrast, AAV-mediated β-synuclein overexpression triggered its spreading to more frontal brain regions. The aggregate formation was investigated as a potential mechanism involved in protein spreading, and consistent with this hypothesis, results showed that overexpression of β-synuclein, but not VAMP2 or SNAP25, in the dorsal medulla oblongata was associated with pronounced protein aggregation. Data indicate that interneuronal protein transfer is not a mere consequence of increased expression or synaptic localization. It is rather promoted by structural/functional characteristics of synuclein proteins that likely include their tendency to form aggregate species.
Keyword(s): Mice (MeSH) ; Animals (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; beta-Synuclein: metabolism (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Brain Stem: pathology (MeSH) ; Vesicle-Associated Membrane Protein 2: metabolism (MeSH) ; Parkinson’s disease ; Parkinson’s disease ; animal models ; oligomerization ; protein spreading ; vagus nerve ; alpha-Synuclein ; beta-Synuclein ; Vesicle-Associated Membrane Protein 2
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