Hyperphosphorylation Results in Tau Dysfunction in DNA Folding and Protection

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.

The herbal compound geniposide rescues formaldehyde-induced apoptosis in N2a neuroblastoma cells

“…Treatment with PNS did not ameliorate the toxic effect of FA ( Figure 6E). Similar to what has been shown previously [25], FA-treated cells grew many short processes and the cell density was significantly decreased (P0.01, n=3) (Figure S2 in Supporting Information). In general, GP and TLJN did not seem to ameliorate the changes in the F-actin morphology induced by FA.…”

Genomic integrity and the ageing brain

“…In a similar vein, unphosphorylated tau, the major constituent of the neurofibrillary tangle, binds to the minor groove of the DNA double helix where its presence protects DNA from oxidative damage 171,172 . Phosphorylation of tau reduces its ability to prevent DNA thermal denaturation and reduces its protection of DNA from reactive oxygen species 173 . Finally, accumulation of α-synuclein in Parkinson disease is associated with increased mtDNA deletions and oxidative DNA damage 174 .…”

Uric formaldehyde levels are negatively correlated with cognitive abilities in healthy older adults

“…In humans, endogenous formaldehyde is typically present in the brain, blood, urine, and other tissues [15,16] . According to the "formaldehyde stress" hypothesis [17] , the abnormal accumulation of endogenous formaldehyde can cause abnormal changes in proteins, resulting in neuronal responses such as tau hyperphosphorylation [18] , DNA damage [19] , reduced long-term potentiation [20] and even cell death [21] , followed by associated dysfunctions. The concentration of endogenous formaldehyde tends toward equilibrium under normal physiological conditions.…”