PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

Krishnan, N., Krishnan, K., Connors, C. R., Choy, M. S., Page, R., Peti, W., Van Aelst, L., Shea, S. D., Tonks, N. K. (2015) PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J Clin Invest, 125 (8). pp. 3163-3177. ISSN 1558-8238 (Electronic)0021-9738 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26214522
DOI: 10.1172/jci80323

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.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders > congenital hereditary genetic diseases > rett syndrome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Huang lab
CSHL labs > Shea lab
CSHL labs > Tonks lab
CSHL labs > Van Aelst lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date Deposited: 30 Jul 2015 14:08
Last Modified: 10 Feb 2017 22:10
PMCID: PMC4563751
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31681

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