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

Abstract

Mutant Tau (MAPT) can lead to frontotemporal lobar degeneration (FTLD). Previous studies associated MAPT mutations and altered function with aneuploidy and chromosome instability in human lymphocytes and in Drosophila development. Here we examine whether FTLD-causing mutations in human MAPT induce aneuploidy and apoptosis in the mammalian brain. First, aneuploidy was found in brain cells from MAPT mutant transgenic mice expressing FTLD mutant human MAPT. Then brain neurons from mice homozygous or heterozygous for the Tau (Mapt) null allele were found to exhibit increasing levels of aneuploidy with decreasing Tau gene dosage. To determine whether aneuploidy leads to neurodegeneration in FTLD, we measured aneuploidy and apoptosis in brain cells from patients with MAPT mutations and identified both increased aneuploidy and apoptosis in the same brain neurons and glia. To determine whether there is a direct relationship between MAPT-induced aneuploidy and apoptosis, we expressed FTLD-causing mutant forms of MAPT in karyotypically normal human cells and found that they cause aneuploidy and mitotic spindle defects that then result in apoptosis. Collectively, our findings reveal a neurodegenerative pathway in FTLD-MAPT in which neurons and glia exhibit mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy, which then lead to apoptosis.

Tau Conformers in FTLD-MAPT  Undergo Liquid-liquid Phase Separation and Perturb the Nuclear Envelope

“…Moreover, live cell imaging analyses indicated that multinucleated giant cells resulted from a failure in cell division ( Fig. S2d and Supplementary Movie 4); as reported by others [51], mitotic abnormalities, chromosome mis-segregation, and aneuploidy were observed in transgenic mice expressing the human P301S FTLD-MAPT mutation.…”

Tau Mutations as a Novel Risk Factor for Cancer—Response

“…Deutschl€ ander and colleagues cited an article demonstrating that MAPT mutations cause aneuploidy in neurons and glia, where the N279K MAPT mutation was analyzed but not reported in detail, as only aggregated data from different missense mutations are shown (5). Although aneuploidy can cause neurodegeneration, it can be linked to cancer in nonneural tissues (6).…”

Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy

“…As summarized above, ploidy reduction/HST could either give rise to daughter cells with a diploid karyotype [37,42] or to daughter cell that are aneuploid and genomically unstable [7,36,39,[45][46][47][48], suggesting that this process might be differentially regulated in distinct cell types. Likewise, aneuploidy and genomic instability appear to be more tolerated in proliferating hepatocytes [36,39,40,[49][50][51], whereas in other cell types, aneuploidy and genomic instability are associated with cell death or senescence [117][118][119][120][121]. Again, it remains to be elucidated how these different cellular outcomes (tolerance/viability vs. apoptosis/senescence) are regulated in distinct cell types.…”

“…In fact, cell fusion-derived aneuploidy and genomic instability are associated with impaired proliferation and overall decreased viability of cells. Several studies demonstrated that aneuploid cells were less proliferative [114,115], more apoptotic [116][117][118], or became senescent [119][120][121], which can most likely be attributed to impaired cellular homeostasis due to altered gene and protein expression levels (for review see [47]). Moreover, even in the context of "cell fusion in cancer", it has been shown that approximately 99% of tumor cell × normal cell hybrids have died or become senescent.…”