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.
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