Hyperphosphorylation Results in Tau Dysfunction in DNA Folding and Protection

Issue title: Tau and Beyond for Alzheimer's Disease: A Special Issue dedicated to Dr. Inge Grundke-Iqbal

Guest editors: Alejandra Alonso and Chengxin Gong

Article type: Research Article

Authors: Lu, Yang^{a; b} | He, Hai-Jin^a | Zhou, Jun^{a; d} | Miao, Jun-Ye^{a; d} | Lu, Jing^a | He, Ying-Ge^a | Pan, Rong^a | Wei, Yan^a | Liu, Ying^a | He, Rong-Qiao^{a; c; *}

Affiliations: [a] State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China | [b] School of Life Science, University of Science and Technology of China, Anhui, China | [c] Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China | [d] University of Chinese Academy of Sciences, Beijing, China

Correspondence: [*] Correspondence to: Rong-Qiao He, State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. Tel.: +86 10 64889876; Fax: +86 10 64875055; E-mail: [email protected]; Yan Wei, State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. Tel.: +86 10 64888531; Fax: +86 10 64875055; E-mail: [email protected].

Abstract: Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While most of the work described so far focused on the relationship between hyperphosphorylation of tau and microtubule disassembly as well as axonal transport impairments, both phenomena ultimately leading to cell death, little work has been done to study the correlation between tau hyperphosphorylation and DNA damage. As we showed in this study, tau hyperphosphorylation and DNA damage co-occurred under formaldehyde treatment in N2a cells, indicating that phosphorylated tau (p-Tau) induced by formaldehyde may be involved in DNA impairment. After phosphorylation, the effect of tau in preventing DNA from thermal denaturation was diminished, its ability to accelerate DNA renaturation was lost, and its function in protecting DNA from reactive oxygen species (ROS) attack was impaired. Thus, p-Tau is not only associated with the disassembly of the microtubule system, but also plays a crucial role in DNA impairment. Hyperphosphorylation-mediated dysfunction of tau protein in prevention of DNA structure from damage under the attack of ROS may provide novel insights into the mechanisms underlying tauopathies.

Keywords: Alzheimer's disease, DNA protection, formaldehyde, GSK-3β, phosphorylation, tau hyperphosphorylation, tau protein, tauopathy

DOI: 10.3233/JAD-130602

Journal: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 551-563, 2013