A neuropathological hallmark in Alzheimer disease (AD) and related disorders is the neurofibrillary tangles, whose main component is hyperphosphorylated tau, a microtubule-binding protein. The formation of the tangles in AD has been shown to be preceded by increased phosphorylation of tau and other proteins on certain serine or threonine residues preceding proline (pSer/Thr-Pro). Although phosphorylation can abolish the ability of tau to bind microtubules and to promote their assembly, little is known about what phosphorylation actually does and how it affects the pathogenesis of the tauopathies. Interestingly, pSer/Thr- Pro motifs in proteins exist in distinct cis and trans conformations, whose conversion is normally inhibited by phosphorylation, but is specifically catalyzed by the prolyl isomerase Pin1. Pin1 activity can restore the microtubule function of phosphorylated tau directly or indirectly via promoting its dephosphorylation in vitro. Significantly, soluble Pin1 is depleted in human AD brains. Importantly, our preliminary results show that the subregional levels of Pin1 expression inversely correlate with the predicted vulnerability to neurodegeneration in normal brain, and also with early neurofibrillary degeneration in AD brain. Furthermore, our preliminary results also show that deletion of Pin1 in mice causes progressive age dependent accumulation of phosphorylated tau and tau filaments as well as neuronal degeneration and loss. Thus, Pin1 is the first gene whose deletion causes age-dependent neurodegeneration and tauopathy and Pin1 mediated post-phosphorylation regulatory mechanism may play a critical role in the development of neurodegeneration. In this proposal, we will first determine how Pin1 affects the development of the tauopathy phenotypes using mouse models by crossbreeding Pin1 null or overexpressing mice with other available transgenic mice that have tan-related phenotypes. Second, we will use cultured cell model systems to determine how Pin1 regulates tau function and affects the development of tau-related phenotypes and to examine the role of Pin1 in ABeta-induced neurotoxicity. Finally, we will investigate whether and how Pin1 function is deregulated during the development of human tauopathies. These studies should help elucidate the molecular mechanisms of AD and related disorders, and may also have novel implications for their therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG022082-01A1
Application #
6725854
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Snyder, Stephen D
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$338,020
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Driver, Jane A; Zhou, Xiao Zhen; Lu, Kun Ping (2015) Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochim Biophys Acta 1850:2069-76
Ma, Suk Ling; Tang, Nelson Leung Sang; Tam, Cindy Woon Chi et al. (2012) A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease. Neurobiol Aging 33:804-13
Lee, Tae Ho; Pastorino, Lucia; Lu, Kun Ping (2011) Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Rev Mol Med 13:e21
Driver, Jane A; Lu, Kun Ping (2010) Pin1: a new genetic link between Alzheimer's disease, cancer and aging. Curr Aging Sci 3:158-65
Ryo, Akihide; Wulf, Gerburg; Lee, Tae Ho et al. (2009) Pinning down HER2-ER crosstalk in SMRT regulation. Trends Biochem Sci 34:162-5
Lim, Jormay; Balastik, Martin; Lee, Tae Ho et al. (2008) Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 118:1877-89
Balastik, Martin; Ferraguti, Francesco; Pires-da Silva, Andre et al. (2008) Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci U S A 105:12016-21
Li, Qi Ming; Tep, Chhavy; Yune, Tae Y et al. (2007) Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J Neurosci 27:8395-404
Lu, Kun Ping; Finn, Greg; Lee, Tae Ho et al. (2007) Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 3:619-29
Balastik, Martin; Lim, Jormay; Pastorino, Lucia et al. (2007) Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism? Biochim Biophys Acta 1772:422-9

Showing the most recent 10 out of 15 publications