Interneuronal In Vivo Transfer of Synaptic Proteins

卷:12

Article

关键词: ALPHA-SYNUCLEIN OLIGOMERS;    BETA-SYNUCLEIN;    MUTATION;    PARKINSON;    PATHOLOGY;    NUCLEUS;    PROPAGATION;    PROJECTIONS;    ANTIBODIES;    SNARE;   

DOI  :  10.3390/cells12040569

来源: SCIE

【 摘 要 】

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.