Post-Translational Modifications and Age-Related Diseases

01/06/2017


Dr. Tae Ho Lee is Assistant Professor of Medicine at Harvard Medical School. He was the guest speaker at a lecture organized by the MGH Gordon Center. Below is his presentation summary.

Dr. Tae Ho Lee delivering his presentation at the MGH Gordon Center

Phosphorylation of proteins is one of the most important post-translational modifications (PTMs) and a key signaling mechanism in diverse physiological and pathological processes. Its deregulation contributes to age-related diseases, notably cancer and Alzheimer’s disease (AD).

AD is characterized by a progressive loss of memory and other cognitive functions. It affects over 44 million people in worldwide and its incidence is expected to triple over the next 30.years. There is therefore an urgent need to understand the mechanisms underlying the degeneration of neuronal cells. The two defining neuropathological features of AD are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). The senile plaques are made of amyloid-β (Aβ), cleaved products of the amyloid precursor protein (APP), whereas the neurofibrillary tangles mainly consist of the microtubule-associated protein tau. Many hypotheses have been proposed to explain the etiology and pathogenesis of AD and related disorders; two dominant theories focus on increased production of Aβ and dysfunction of tau. However, currently the pathogenic mechanisms are still not fully understood and there is no effective therapy. Therefore, the ability to define regulatory mechanisms controlling APP processing and tau function will be critical for elucidating the pathogenesis and for designing strategies for preventing and/or treating neurodegenerative diseases.

Death-associated protein kinase 1 (DAPK1) is a death domain-containing calcium/ calmodulinregulated serine/threonine kinase and plays an important role in regulating neuronal function. We demonstrated here that DAPK1 expression is dramatically up-regulated in the 75% hippocampi of AD patients compared with age-matched normal subjects. Moreover, we showed that DAPK1 regulates tau toxicity in modulating microtubule assembly and neuronal differentiation, and DAPK1 overexpression increases tau phosphorylation at multiple AD-related sites in cells and animal models. We also found that DAPK1 increases Aβ secretion in a kinase activity-dependent manner. In addition, the levels of insoluble Aβ and amyloidogenic APP processing are significantly reduced in APP-overexpression/DAPK1-knockout mice brain. Finally, we identified novel DAPK1 substrates that are involved in neuronal cell death and AD including N-myc downstream-regulated gene 2 (NDRG2). Together, these results suggest that DAPK1 may be a critical regulator of tau phosphorylation, APP processing, and neuronal cell death and DAPK1 deregulation may contribute to AD progression. Therefore, DAPK1 may serve a potential therapeutic target for AD.

Comments are closed.