Neuropathology in Mice Expressing Mouse Alpha-Synuclein
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Le résumé fourni par la source
α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Neuropathology in Mice Expressing Mouse Alpha-Synuclein
- Date Crossref
- 26/09/2011
- Éditeur
- Public Library of Science (PLoS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Novartis (Switzerland) pays non établi dans la noticeEntreprise
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Trinity College Dublin pays non établi dans la noticeUniversité ou école supérieure
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University of Basel Neurobiology Biozentrum pays non établi dans la noticeUniversité ou école supérieure
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German Center for Neurodegenerative Diseases pays non établi dans la noticeStructure de recherche
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Hertie Institute for Clinical Brain Research pays non établi dans la noticeInstitution
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University of Tübingen Department of Neurodegeneration pays non établi dans la noticeUniversité ou école supérieure
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Novartis Institutes for BioMedical Research pays non établi dans la noticeStructure de recherche
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School of Medicine Department of Physiology pays non établi dans la noticeUniversité ou école supérieure
Novartis (Switzerland), Trinity College Dublin et Neurobiology Biozentrum — University of Basel, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.