# PTPRD ligands for stimulant and opiate use disorders

> **NIH NIH U01** · BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX · 2020 · $315,055

## Abstract

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.

## Key facts

- **NIH application ID:** 10120215
- **Project number:** 3U01DA047713-02S1
- **Recipient organization:** BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
- **Principal Investigator:** George Richard Uhl
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,055
- **Award type:** 3
- **Project period:** 2019-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120215

## Citation

> US National Institutes of Health, RePORTER application 10120215, PTPRD ligands for stimulant and opiate use disorders (3U01DA047713-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120215. Licensed CC0.

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