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 1

Mecp2-mutant mouse model displayed impaired insulin signaling and glucose metabolism.

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Mecp2-mutant mouse model displayed impaired insulin signaling and gluco...
(A) GTT results for WT and Mecp2-mutant mice: 4-week-old male WT (n = 10) (black) or Mecp2–/y (n = 10) (gray) mice were administered D-glucose (2 mg/g BW), and blood glucose was monitored (left panel). GTT results for 8-week-old female WT (n = 10) (black) and Mecp2–/+ (n = 10) (gray) mice are shown on the right. Statistical analysis was performed using 2-way ANOVA (**P < 0.01, *P < 0.05). (B) ITT results for WT and Mecp2-mutant mice: WT (n = 10; black) or Mecp2–/y (n = 10; gray) mice were administered insulin (0.75 mU/g BW), and blood glucose was monitored (left panel). ITT results for 8-week-old female Mecp2–/+ (n = 10; gray) and WT (n = 10; black) mice are shown on the right. Statistical analysis was performed using 2-way ANOVA (P = 0.1). (C) Representative immunoblots for insulin signaling in WT and Mecp2–/y forebrain tissue lysates. Immunoblots showing insulin-induced tyrosine phosphorylation of IR-β and IRS1, threonine (T308) and serine (S473) phosphorylation of AKT, phosphorylation of FOXO1 and GSK3β, and their total protein levels in forebrain tissue lysates from 4-week-old WT and Mecp2–/y mice. For insulin stimulation, animals were treated with insulin (0.75 mU/g, i.p.) for 15 minutes. All blots are representative of experiments performed 3 times. (D) Representative immunoblots for insulin signaling in WT and Mecp2–/+ forebrain tissue lysates. Immunoblots show insulin-induced tyrosine phosphorylation of IR-β and IRS1, T308 phosphorylation of AKT, and their total protein levels in forebrain tissue lysates from 8-week-old WT and Mecp2–/+ mice. For insulin stimulation, animals were treated with insulin (0.75 mU/g, i.p.) for 15 minutes. All blots are representative of experiments performed 3 times.