Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, TAU PROMOTES NEURODEGENERATION, CELL-CYCLE ACTIVATION, COPY-NUMBER VARIATION, ALZHEIMERS-DISEASE, GENE-EXPRESSION, PROTEIN, PHOSPHORYLATION, MUTATIONS, MITOSIS, SPINDLE, Aneuploidy, Animals, Cell Line, Cell Survival, Gene Expression Regulation, Developmental, Humans, Mitosis, Mutation, Neural Stem Cells, Neurons, Phenotype, Photoreceptor Cells, Protein Isoforms, Tauopathies, tau Proteins

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.