Mutazioni nel gene tau associate ad instabilità cromosomica: un nuovo ruolo della proteina tau. Studio nell'uomo

Tau is a microtubule associated protein that promotes assembly and stabilization of cytoskeleton microtubules (MT) required for morphogenesis and axonal transport. It is mostly expressed in neuronal and glial cells but it is also present in non-neuronal cells such as fibroblast, lymphocytes and lymphoblasts where it can play further functions. Six major tau isoforms are expressed in adult human brain, as a result of alternative mRNA splicing of exons 2, 3 and 10 of MAPT, a gene located on 17q21.1 where it occupies over 100 kb. Tau is subjected to different post-translational modifications, among which phosphorylation is known to negatively regulate its ability to bind to MT. In fact, in cycling cells, tau has a low level of phosphorylation and is mostly bound to MT during interphase, while at the onset of mitosis, it became highly phosphorylated reducing its affinity to MT and permitting their dinamic instability required for the rapid mitotic movements. Abnormal hyperphosphorylation of tau causes disruption of cytoskeleton and deposition of hyperphosphorylated tau filaments in neuron and glial cells, resulting in cerebral atrophy and dementia, hallmarks of Alzheimer’s disease as well as of the so-called tauopathies, adult-onset diseases that can be of genetic origin and caused by dominant mutations in MAPT, among which frontotemporal dementia (FTD) is the most frequent. Missense, deletion and silent mutations have been reported in the coding region of MAPT, with additional mutations in the intronic region close to the 5’ splice site of exon 10. Very recently it has been proposed an involvement of tau in chromosome stability, based on its localization both in the interphasic nucleus and along mitotic chromosomes and on the presence of several chromosome and chromatin aberrations in fibroblasts and lymphocytes of patients affected by FTD carrying P301L mutation (Rossi G et al., 2008). In the present study, in order to establish whether chromosomal aberrations are a general phenomenon in tauopathies rather than a unique feature of the P301L mutation, we investigated these alterations in somatic cells of patients bearing different MAPT mutations with standard (karyotype) and molecular (array-CGH) cytogenetic techniques. Furthermore, since the observed chromosome instability resembled some features of what is seen in syndromes caused by mutations in genes involved in the DNA repair systems, we tested the response of mutated lymphoblastoid cell lines to genotoxic agents, able to induce single- and double-strand breaks. Lymphocytes and fibroblasts of patients showed a significantly higher level of structural aberrations and total aneuploidy compared to controls. We observed also a high level of premature chromatid division (pcd), that is correlated with chromosome segregation defects and aneuploidies, and abnormal nuclei. Condensations defects were also widely present in the patients and not in the controls, thus a role of tau in condensation or decondensation of chromatin may be hypothesized. Analyzing lymphoblastoid cell lines treated with genotoxic agents, we have not yet demonstrated an involvement of the protein in DNA repair systems, but these results need to be confirmed. Our findings indicate that tau may be involved in chromosome segregation and stabilization of chromatin structure most likely through interactions with both microtubules and chromatin itself. The occurrence of numerical chromosome aberrations in FTD patients is likely due, at least in part, to misfunction of tau as a MT associated protein, since the mutations studied decrease the binding of the protein to MT, producing an instable spindle. Fragility and alterations in chromosome structure due to mutated nuclear tau may slowly accumulate in postmitotic cells and lead to abnormal regulation of gene expression with subsequent neuronal damage and death. The evidence of a role of tau in the functioning of mitotic spindle and stability of chromatin points to this protein as a possible component of the complex system guarding genome stability.