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

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.

Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations

“…Specifically, a study by Bougé and Parmentier (2016) showed that excess Tau causes mitotic spindle defects, aneuploidy, and apoptosis through inhibition of the microtubule-dependent motor protein Kinesin-5/Eg5. Similar results have been observed by Malmanche et al. (2017) , who examined photoreceptors and brain neurons in Drosophila and found that adult-onset neurodegeneration mediated by MAPT overexpression included the generation of aneuploid cells ( Malmanche et al.…”

Atypical, non-standard functions of the microtubule associated Tau protein

“…Evidence arguing that a fruitful approach does not necessitate knowledge of isoform-specific subcellular localization was presented from Amrit Mudher suggesting that human Tau isoforms in the Drosophila model present differential phenotypes consistent with unique isoform-specific pathophysiological functions [ 40 ]. Consistent with this view, recently published work by Bart Dermaut described a pathological role for the 4R, but not the 3R, Tau during Drosophila development [ 41 ], a further demonstration of the utility of this model in addressing such questions in vivo.…”

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer’s Disease

“…While Tau is most well-known for the stabilization of microtubules, several studies have shown that Tau is also localized to the nucleus in heterochromatic regions, most notably at nucleolar organizing regions (Loomis et al, 1990 ; Sjöberg et al, 2006 ; Rossi et al, 2008 ). The role of Tau at these regions is likely related to mitotic progression, expression of an adult form of Tau during Drosophila development leads to delayed mitotic progression in neural progenitors, resulting in aneuploidy in post-mitotic cells and reduced lifespan (Malmanche et al, 2017 ). Of interest, Rossi et al ( 2008 ) found that frontotemporal dementia patients expressing mutant Tau had chromosome abnormalities in fibroblasts and lymphocytes; these included metaphase chromatid breaks, abnormal metaphase chromatin threads, chromosome deletions and decondensing of the prophase nucleus.…”