PTP1B inhibition suggests a therapeutic strategy for Rett syndrome
Navasona Krishnan, … , Stephen D. Shea, Nicholas K. Tonks
Navasona Krishnan, … , Stephen D. Shea, Nicholas K. Tonks
Published July 27, 2015
Citation Information: J Clin Invest. 2015;125(8):3163-3177. https://doi.org/10.1172/JCI80323.
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Research Article Neuroscience

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

Abstract

The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG–binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2–/y) mice and improved behavior in female heterozygous (Mecp2–/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs.

Authors

Navasona Krishnan, Keerthi Krishnan, Christopher R. Connors, Meng S. Choy, Rebecca Page, Wolfgang Peti, Linda Van Aelst, Stephen D. Shea, Nicholas K. Tonks

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Figure 3

Biochemical characterization of the PTP1B inhibitor CPT157633.

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Biochemical characterization of the PTP1B inhibitor CPT157633. (A) Chemi...
(A) Chemical structure of CPT157633. (B) Lineweaver-Burk plot for PTP1B1–405 showing 1/rate versus 1/substrate at varying concentrations of CPT157633: 0 (white circles), 25 nM (black squares), 50 nM (black triangles), and 100 nM (black diamonds). The KI was calculated to be 45 nM (n = 3, data are representative of 3 independent experiments). (C) PTP1B inhibition by CPT157633 was characterized using 32P-RCML as a substrate. 32P-RCML (0–1 μM) was titrated against PTP1B (10 nM) in the absence and presence of CPT157633 (100 nM) (n = 3, data are representative of 3 independent experiments). (D) Phosphatase activity of a panel of PTPs (10 nM) was tested in the absence and presence of CPT157633 (100 nM) using pNPP (2 mM) as a substrate (n = 3, data are representative of 3 independent experiments). (E) Titration of CPT157633 resulted mainly in CSPs localized to the residues that compose the PTP1B active site. Combined 1H/15N CSPs versus residues are shown, and the secondary structure of PTP1B is indicated. Blue indicates residues that are in fast exchange, and red indicates residues that broaden beyond detectability upon addition of CPT157633 or that were previously not assigned in the CPT157633 free form of PTP1B. (F) Overlay of PTP1B (gray surface) bound to CPT157633 inhibitor (orange). CSPs that accompanied binding of CPT157633 to PTP1B are mapped on to the structure (pink). (G) Electrostatic interactions between the CPT157633 inhibitor and the PTP1B active site loop (electrostatic interactions are indicated by black dashed lines).