期刊
CELLS
卷 12, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cells12040569
关键词
protein spreading; oligomerization; animal models; Parkinson's disease; vagus nerve
类别
Neuron-to-neuron transfer of pathogenic alpha-synuclein is likely relevant to Parkinson's disease development, and the spreading ability of alpha-synuclein can be reproduced by injecting AAV vectors encoding for alpha-synuclein into the mouse vagus nerve. This study investigated whether other proteins share this spreading ability. Results showed that beta-synuclein, but not VAMP2 or SNAP25, can spread to more frontal brain regions, and protein aggregation may be involved in this spreading mechanism.
Neuron-to-neuron transfer of pathogenic alpha-synuclein species is a mechanism of likely relevance to Parkinson's disease development. Experimentally, interneuronal alpha-synuclein spreading from the low brainstem toward higher brain regions can be reproduced by the administration of AAV vectors encoding for alpha-synuclein into the mouse vagus nerve. The aim of this study was to determine whether alpha-synuclein's spreading ability is shared by other proteins. Given alpha-synuclein synaptic localization, experiments involved intravagal injections of AAVs encoding for other synaptic proteins, beta-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 beta-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 beta-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.
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