Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death

Abstract

In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT)-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11). We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases.

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

“…It has been recently reported that 4R-Tau over expression in Drosophila wing discs induces a mitotic delay characterized by the formation of monopolar spindles leading to aneuploidy and cell death in a non-neuronal cell context9. In addition, the authors observed a similar spindle phenotype within the larval neuronal progenitors but without further investigation.…”

“…Third, in mice, expression of similar Tau mutations also induces genomic instability ranging from chromosome rearrangements to aneuploidy8. Finally, a recent report showed that human Tau overexpression in Drosophila can induce a mitotic block leading to aneuploidy9.…”

Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss

“…Accordingly, a recent study found that tau can also inhibit Eg5 activity; thus, Ab may inhibit Eg5 not only directly but also indirectly via regulation of tau (Bougé and Parmentier, 2016). Overall, it is likely that there is very complex interplay between Ab, tau, and Eg5 in the regulation of neuronal function, which definitely warrants future investigation.…”

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

“…Consequently, increased level of aneuploidy in splenic lymphocytes of tauopathy transgenic mouse models have recently been reported (Rossi et al, 2014). In Drosophila, human Tau excess impairs mitosis, leading to aneuploidy and cell death (Bouge and Parmentier, 2016). Plausibly, abnormal activation of SRPK2 may phosphorylate numerous substrates including delta-secretase, Tau, SR domain containing splicing factors, coordinating the AD pathologies, coupling defective cell cycle machinery to neuronal cell death.…”