Mutations in MAPT Gene Cause Chromosome Instability and Introduce Copy Number Variations Widely in the Genome

Abstract

In addition to the main function of promoting polymerization and stabilization of microtubules, other roles are being attributed to tau, now considered a multifunctional protein. In particular, previous studies suggest that tau is involved in chromosome stability and genome protection. We performed cytogenetic analysis, including molecular karyotyping, on lymphocytes and fibroblasts from patients affected by frontotemporal lobar degeneration carrying different mutations in the microtubule-associated protein tau gene, to investigate the effects of these mutations on genome stability. Furthermore, we analyzed the response of mutated lymphoblastoid cell lines to genotoxic agents to evaluate the participation of tau to DNA repair systems. We found a significantly higher level of chromosome aberrations in mutated than in control cells. Mutated lymphocytes showed higher percentages of stable lesions, clonal and total aneuploidy (medians: 2 versus 0, p $\ll$ 0.01; 1.5 versus 0, p $\ll$ 0.01; 16.5 versus 0, p $\ll$ 0.01, respectively). Fibroblasts of patients showed higher percentages of stable lesions, structural aberrations and total aneuploidy (medians: 0 versus 0, p = 0.03; 5.8 versus 0, p = 0.02; 26.5 versus 12.6, p $\ll$ 0.01, respectively). In addition, the in depth analysis of DNA copy number variations showed a higher tendency to non-allelic homologous recombination in mutated cells. Finally, while our analysis did not support an involvement of tau in DNA repair systems, it revealed its role in stabilization of chromatin. In summary, our findings indicate a role of tau in genome and chromosome stability that can be ascribed to its function as a microtubule-associated protein as well as a protein protecting chromatin integrity through interaction with DNA.

Roles of tau protein in health and disease

“…Similarly, tau knockout neurons are more susceptible to hyperthermia-induced DNA and RNA breakage in comparison to their wild-type counterparts [495]. Furthermore, tau may be involved not only in DNA protection, but also in DNA repair mechanisms [495], although this remains controversial since others have reported that tau is not involved in DNA repair [421]. …”

“…Tau binds to the AT-rich minor groove of DNA through its proline-rich and microtubule binding domains [403, 421]. The typical function of minor groove architectural binding proteins, such as high mobility group proteins, is to alter DNA conformation, causing it to unwind [34].…”

“…These findings support the view that tau may have a role as an epigenetic regulator of gene expression. In addition, tau is reported to contribute to chromosomal stability and to participate in the processing and/or silencing of ribosomal RNA [309, 421]. …”

“…In fibroblasts and lymphocytes from FTLD-tau affected patients, a series of cell deficits are observed in cells bearing tau mutants, including increased susceptibility of the cells to stress, altered gene transcription, and chromosome aberrations [421, 422]. In contrast, the impact of phosphorylation on the nuclear function of tau is more complex.…”

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

“…First, Tau has been reported to have a DNA-protective function in the nucleus45. Second, it has been shown that aneuploidy is present in peripheral cells and in primary fibroblast cell cultures from patients carrying known Tauopathies mutations67. Third, in mice, expression of similar Tau mutations also induces genomic instability ranging from chromosome rearrangements to aneuploidy8.…”