Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson's disease.

Details

Serval ID
serval:BIB_AA6B6F98A17F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson's disease.
Journal
NPJ Parkinson's disease
Author(s)
Prymaczok N.C., De Francesco P.N., Mazzetti S., Humbert-Claude M., Tenenbaum L., Cappelletti G., Masliah E., Perello M., Riek R., Gerez J.A.
ISSN
2373-8057 (Print)
ISSN-L
2373-8057
Publication state
Published
Issued date
06/01/2024
Peer-reviewed
Oui
Volume
10
Number
1
Pages
10
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Parkinson's disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson's disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson's disease. In summary, a novel animal model of Parkinson's disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson's disease in mice.
Pubmed
Web of science
Open Access
Yes
Create date
08/01/2024 17:53
Last modification date
27/01/2024 8:36
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