DNA double-strand break repair defects and tau pathology in neurons|～Discovery of New Physiological Functions of Tau～

DNA double-strand break repair defects and tau pathology in neurons
～Discovery of New Physiological Functions of Tau～

Megumi Asada-Utsugi^1）, Atsushi Shibata^2）, Makoto Urushitani^1）3）

^1）Department of Neurology, Molecular Neuroscience Research Center Shiga University of Medical Science
^2）Division of Molecular Oncological Pharmacy Keio University Faculty of Pharmacy
^3）Department of Neurology, Shiga University of Medical Science

DNA double-strand break （DSB） is the most severe form of DNA damage and accumulates with age, amyloid β, neuronal activity, and excitotoxicity.　We focused on the relationship between the DSB repair system and the tau protein in neurons.　Neurons cannot cause cell division, so they are arrested in the G0 phase.　Therefore, the DSB repair system is essential for neurons, but it is unclear how neurons use the DSB repair system.　In dividing cells, cytoskeletal proteins play a crucial role in DSB repair.　Tau is a microtubule-associated protein, so we investigate whether DSB is involved in tau pathologies in Alzheimer's disease （AD）.　We revealed increasing DSB in the brains of AD patients.　In in vitro studies using primary mouse cortical neurons, non-phosphorylated tau accumulates in the perinuclear membrane with the tubulin after DSB induction.　Then, excessive DSB accumulation enhanced phosphorylated tau and neuronal cell death.
Moreover, the knockdown experiment of endogenous mouse tau showed the protective role of tau in a short time of DNA repair.　Double exposure of microtubule disassembly and the DSB accumulated phosphorylated-tau aggregation in the neurons.　We discuss the DSB repair system of neurons with our data and the latest DSB repair reports.

Address correspondence to Dr. Megumi Asada-Utsugi, Department of Neurology, Molecular Neuroscience Research Center Shiga University of Medical Science （Setatsukinowa-cho, Otsu, Shiga, Japan）