Mutazioni nel gene tau associate ad instabilità cromosomica: un nuovo ruolo della proteina tau. Studio nel topo transgenico

Tau is a major microtubule-associated protein of neurons that promotes assembly and stabilization of cytoskeleton microtubules. Under physiological conditions, tau is mainly located to the axons of neurons and is critical in the process of neural outgrowth and axonal integrity. The protein is also present in non-neural cells, such as fibroblasts and lymphocytes. Under pathological conditions, tau becomes hyperphosphorylated, which means a higher degree of phosphorylation at physiological sites, as well as de novo phosphorylation at additional, pathological sites. Phosphorylation decreases the binding of tau to microtubules and its translocation to the somatodendritic compartment where it forms filaments, which assemble into macroscopically visible structures called neurofibrillary tangles (NFTs). Tauophaties comprise a diverse group of adult-onset diseases that are characterized by disruption of cytoskeleton and deposition of hyperphosphorilated tau filaments in neurons and sometimes in glia, resulting in cerebral atrophy and dementia. Tauophaties of genetic origin are caused by dominant mutations in the tau gene; the most studied is the P301L mutation, associated with frontotemporal dementia (FTD) phenotype. Transgenic mice expressing human tau with P301L mutation develop NFTs composed of filamentous tau, similar to straight filaments in the human neurodegenerative disease, that are concentrated in the spinal cord, brain stem, cerebellar deep nuclei, diencephalon and basal telencephalon. In addition there is neural loss (almost 50% in the spinal cord), reactive gliosis, axonal degeneration and glial inclusions. The aim of this study was to investigate the role of tau protein in chromosome stability, by means of its interaction with both microtubules and chromatin, through cytogenetic analysis on cells derived from central nervous system (subventricular zone) and from other tissues (splenic lymphocytes and fibroblasts) of transgenic mice expressing human tau with P301L mutation. We performed standard cytogenetic analysis on splenic lymphocytes and, most notably, on neural stem cells (NSC) from transgenic mice expressing the human tau with the P301L mutation (strain JNPL3). Transgenic mice expressing wild-type human tau (strain JN25) and non transgenic mice of the same strain were analyzed as controls. Analysis of splenic lymphocytes showed a significant difference in the level of aneuploidy between JNPL3 and JN25 mice as well as in non-transgenic controls (Student’s t-test, p