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Sci Rep. 2017 Jan 23;7:40764. doi: 10.1038/srep40764.

Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models.

Malmanche N1,2,3, Dourlen P1,2,3, Gistelinck M4,5, Demiautte F1,2,3, Link N6, Dupont C1,2,3, Vanden Broeck L4,5, Werkmeister E2,3,7,8,9, Amouyel P1,2,3, Bongiovanni A2,3,7,8,9, Bauderlique H2,3,7,8,9, Moechars D10, Royou A11,12,13, Bellen HJ6,14,15,16,17, Lafont F7,8,9, Callaerts P4,5, Lambert JC1,2,3, Dermaut B1,2,3,18.

Author information

1
Inserm UMR1167, Laboratoire d'Excellence Distalz, Lille, F59000, France.
2
Institut Pasteur de Lille, Longevity Research Center, Lille, F59000, France.
3
Université de Lille, Lille, F59000, France.
4
Laboratory of Behavioral and Developmental Genetics, Center for Human Genetics, KU Leuven, Leuven, 3000, Belgium.
5
VIB Center for the Biology of Disease, Leuven, 3000, Belgium.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Center for Infection and Immunity of Lille, 59019, France.
8
Inserm UMR1019, Lille, 59019, France.
9
CNRS UMR8204, Lille, 59019, France.
10
Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, 2340, Belgium.
11
CNRS UMR5095, Pessac, 33607, France.
12
Institut Européen de Chimie et Biologie, Pessac, 33607, France.
13
Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, Pessac, 33607, France.
14
Howard Hughes Medical Institute, Houston, TX 77030, USA.
15
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
16
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
17
Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA.
18
Center for Medical Genetics, Ghent University Hospital, Ghent University, Gent, 9000, Belgium.

Abstract

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.

PMID:
28112163
PMCID:
PMC5256094
DOI:
10.1038/srep40764
[Indexed for MEDLINE]
Free PMC Article

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