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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
5R00AG033104-05
Application #
8531104
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$235,307
Indirect Cost
$100,073
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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