PTPRD ligands for stimulant and opiate use disorders

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Pathological tau hyperphosphorylation and neurofibrillary pathology are major Alzheimer's disease (AD) pathophysiological elements that correlate with clinical dementia. Activities of several kinases that hyperphosphorylate tau, including cyclin dependent CDK5, glycogen synthase GSK3α and GSK3β are enhanced by phosphorylation of their own tyrosines (pY15, pY279 and pY216). Tyrosine kinases that phosphorylate and activate these three tau-phosphorylating kinases are known. However, the tyrosine phosphatase(s) that dephosphorylate and thus reduce activities of brain CDK5, GSK3α and GSK3β have not been reported. Several lines of evidence now support PTPRD, a receptor type protein tyrosine phosphatase, as a major contributor to dephosphorylating tau-phosphorylating enzymes including CDK5, GSK3α and GSK3β. We will test the hypothesis that PTPRD contributes to regulation of CDK5, GSK3α and GSK3β activities in ways that make PTPRD a novel, multifactorial, druggable contributor to tau pathophysiology in AD. We are fortunate that work developing a PTPRD phosphatase inhibitor to reduce reward from addictive substances is funded by a NIDA parent grant U01DA047713 that provides an exceptionally solid platform for the current supplement proposal. In vitro, we will test activities of CDK5, GSK3α and GSK3β wildtype, mutant and control/comparison phosphopeptides at wildtype/mutant human D1 and D1 + D2 phosphatase domains from PTPRD and other tyrosine phosphatases. We will seek potent interactions between wildtype PTPRD phosphatase and pY15 CDK5, pY279 GSK3α and/or pY216 GSK3β phosphopeptides vs lower potency interactions with dephosphorylated/mutant/control peptides, PTPRD mutants and other tyrosine phosphatases. In vivo, we will characterize effects of genetically or pharmacologically altered PTPRD activity on brain CDK5, GSK3α and GSK3β tyrosine phosphorylation in mice. In pilot projects, we will a) cross 3xTg-AD mice with PTPRD knockouts to seek suitability of these “4xTg-AD” mice for studies of effects on tau pathology in aging and b) synthesize and model NF504, NF506 and other potential positive allosteric modulators of PTPRD's phosphatase for future tests of our innovative hypotheses. This work will aid new understanding of Alzheimer's disease neurofibrillary pathology and help to define PTPRD as a novel therapeutic target.