Telomeres are specialized structures located at tlie ends of eukaryotic chromosomes consisting of simple DNA repeats and specific binding proteins, preventing degradation and end fusion. Recently, accelerated telomere shortening has been implicated in premature aging and also observed in Alzheimer's disease (AD). However, little is known about how telomeres are regulated in neurons during aging and how its deregulation contributes to the development of AD. Pini, a peptidyl-prolyl cis/trans isomerase, regulates protein function by isomerizing specific phosphorylated Ser/Thr-Pro bonds. Pin1-induced conformational changes after phosphorylation are important in many cellular processes, including neuronal survival. Significantly, Pini deregulation can play an important role In some pathological conditions such as premature aging and AD. My own preliminary data showed that Pin1 interacted with the conserved phosphorylated Thr149-Pro motif in the telomere DNA-binding protein TRF1, which is a major regulator of telomere length by limiting telomere elongation by telomerase when telomeres reach certain length. Furthermore, inhibition of Pini rendered TRF1 resistant to degradation and also caused telomere shortening. Moreover, Pini knockout in mice leads to elevated TRF1 levels, accelerated telomere shortening and a range of premature aging phenotypes within single generation, suggesting that Pin1 is a central regulator of TRF1 and telomere maintenance. These results led me to hypothesize that Pin 1-dependent regulation of TRF1 and telomere maintenance might play a major role in the development of aging and AD. In the mentored phase of this award, I plan to develop my skills in the administration of genetic material to the murine brain, focusing on the role of Pin1 in telomere maintenance in neurons during aging and AD using various mouse models available in my mentor's laboratory. In the independent phase of the award, I will investigate molecular mechanisms by which Pini regulates TRF1 and telomere maintenance as well as by which Pin1 itself is regulated by phosphorylation during aging and AD. These studies should provide novel insight into telomere maintenance during aging and AD, and might have novel implications for developing new therapies.

Public Health Relevance

AD is the most common form of dementia, affecting millions people in the world and with only limited treatments. My goal is to identify novel molecular mechanisms leading to development of AD by focusing on telomere biology. This study will have a significant impact upon our basic understanding of AD, and might eventually facilitate the development of novel treatments of AD via targeting of telomere maintenance.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Transition Award (R00)
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National Institute on Aging Initial Review Group (NIA)
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Wise, Bradley C
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Beth Israel Deaconess Medical Center
United States
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You, Mi-Hyeon; Kim, Byeong Mo; Chen, Chun-Hau et al. (2017) Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death. Cell Death Differ 24:238-250
Kim, Byeong Mo; You, Mi-Hyeon; Chen, Chun-Hau et al. (2016) Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein. Hum Mol Genet 25:2498-2513
Chen, Chun-Hau; Li, Wenzong; Sultana, Rukhsana et al. (2015) Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis 76:13-23
Kim, B M; You, M-H; Chen, C-H et al. (2014) Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function. Cell Death Dis 5:e1237
Chen, Chun-Hau; Chang, Che-Chang; Lee, Tae Ho et al. (2013) SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer Res 73:3951-62