Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep40764
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Funding
- Agency for Innovation by Science and Technology (IWT) in Flanders, Belgium
- FWO-F
- Foundation for Alzheimer Research (SAO/FRMA)
- Belgian Science Policy Office (BELSPO)
- IWT
- Janssen Pharmaceutica in Belgium
- Inserm
- Institute Pasteur de Lille
- Universite de Lille
- DN2M (Demences des maladies Neurologiques et Mentales), Etat Region Nord/Pas-de-Calais
- European Regional Development Funds ERDF [11005007]
- French National Foundation on Alzheimer's disease and related disorders
- DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) - LABEX program (laboratory of excellence program investment for the future)
- INSTALZ, an EU Joint Programme - Neurodegenerative Disease Research (JPND) project
- Belgium, Research Foundation Flander
- Denmark, Innovation Fund Denmark
- France, Agence Nationale de la Recherche
- Sweden, Swedish Research Council
- United Kingdom, Medical Research Council
- European Union [643417]
- Robert A. and Renee E. Belfer Family Foundation
- NINDS [F32NS092270]
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Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development.
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