Methylation and Phosphorylation: A Tangled Relationship?

Abstract

Many neurodegenerative diseases are associated with distinctive brain lesions. One particular group of heterogeneous dementias and movement disorders is characterized by intracellular accumulations of abnormal filaments called neurofibrillary tangles (NFT), formed by the microtubule-associated protein tau. These neurodegenerative tauopathies include Pick disease and Alzheimer disease (AD), but the term also encompasses a range of other clinical conditions that share a common end-point: neurodegeneration with pathological tau accumulation (1). Tau occurs predominantly in neuronal axons, where it binds to microtubules and regulates their length and “treadmilling” dynamics. Tight regulation of microtubule activity is critical to cell viability, and fine regulation of tau is likely to be equally important (2). Tau activity is modulated by phosphorylation, and the ability of tau to bind to and stabilize microtubules correlates inversely with its degree of phosphorylation. This relationship has led to the suggestion of a role for tau in the adaptive response of neurons to stress (3). Tau phosphorylation may represent a physiological and reversible process integral to the stress response system. For example, in animal models, tau phosphorylation occurs in response to ether anesthesia, cold-water stress, and starvation (4). Tau is highly phosphorylated in several neurodegenerative diseases associated with NFT formation. Disordered phosphorylation disrupts the normal colocalization of tau with microtubules, leading to further phosphorylation at fibrillogenic sites and/or cleavage by caspases. This process increases the probability of tau-tau interactions leading to the formation of paired …