Tau and DNA Damage in Neurodegeneration

Abstract

Neurodegenerative disorders are a family of incurable conditions. Among them, Alzheimer's disease and tauopathies are the most common. Pathological features of these two disorders are synaptic loss, neuronal cell death and increased DNA damage. A key pathological protein for the onset and progression of the conditions is the protein tau, a microtubule-binding protein highly expressed in neurons and encoded by the MAPT (microtubule-associated protein tau) gene. Tau is predominantly a cytosolic protein that interacts with numerous other proteins and molecules. Recent findings, however, have highlighted new and unexpected roles for tau in the nucleus of neuronal cells. This review summarizes the functions of tau in the metabolism of DNA, describing them in the context of the disorders.

Keywords: Alzheimer’s disease; DNA damage; tau.

Figure 1

Types of DNA lesions, their DNA repair pathways and possible connections with Alzheimer’s Disease (AD). The principle and well-characterized DNA damage repair pathways are double-strand break repair (DSBR), nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR). DSBR- and BER-specific mutations have been associated with AD (red).

Figure 2

Tau, interaction with DNA damage and AD progression. DNA insults, such as caused by reactive oxygen species (ROS), bacterial infections and tau mutations, can cause hyperphosphorylation of tau and the formation of neurofibrillary tangles (NFT) in AD-induced progression. This particular situation drastically negatively influences DNA damages and repair pathways (Red).