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.
Highlights
To its predicted MAP activity, Tau is increasingly acknowledged for its multi-functional protein activities[3]
In Drosophila, studies of tauopathy models based on panneuronal expression of human 4R-Tau with or without clinical FTD-causing mutations, have shown induction of post-mitotic cell cycle re-entry, mitochondrial toxicity, chromatin relaxation and lamin dysfunction[13,14,15,16,17]. These proposed pathways are assumed to take place in a normally developed and genomically stable postnatal or adult brain. In these panneuronal Drosophila tauopathy models, induction of transgene expression relies on the binary Gal4/UAS system with Tau expression being induced by the Gal[4] transcription factor that is under the control of the panneuronal Elav promoter
We report that 4R-Tau-mediated adult phenotypes in established Drosophila tauopathy models are pre-determined during larval development where 4R-Tau expression affects normal mitotic progression inducing severe spindle morphology and chromosome segregation defects
Summary
To its predicted MAP activity, Tau is increasingly acknowledged for its multi-functional protein activities[3]. In Drosophila, studies of tauopathy models based on panneuronal expression of human 4R-Tau with or without clinical FTD-causing mutations, have shown induction of post-mitotic cell cycle re-entry, mitochondrial toxicity, chromatin relaxation and lamin dysfunction[13,14,15,16,17]. These proposed pathways are assumed to take place in a normally developed and genomically stable postnatal or adult brain. Neuroblastoma cell lines allowing conditional expression of 4R wild type and clinical Tau mutations causing early-onset FTD, induced identical mitotic spindle defects, suggesting that our fly results could be relevant in a human disease context
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