PTP1B inhibition suggests a therapeutic strategy for Rett syndrome
Navasona Krishnan, Keerthi Krishnan, Christopher R. Connors, Meng S. Choy, Rebecca Page, Wolfgang Peti, Linda Van Aelst, Stephen D. Shea, Nicholas K. Tonks
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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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 2

Mecp2-mutant mice expressed higher levels of PTP1B.

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Mecp2-mutant mice expressed higher levels of PTP1B. (A) Total RNA obtai...
(A) Total RNA obtained from WT and Mecp2–/y mice was reverse transcribed and the cDNA used in qPCR analysis. The relative change in gene expression in the insulin-signaling pathway in Mecp2–/y mice forebrain compared with WT was measured and the data normalized to Gapdh expression (n = 3, data represent the mean ± SEM). (B) A series of reporter constructs containing different lengths of the PTPN1 promoter were expressed in HEK293T cells, together with control or MECP2-E1– or MECP2-E2–expressing plasmids. Expression of either isoform MECP2-E1 (light gray) or MECP2-E2 (dark gray) suppressed PTPN1 promoter activity (n = 3, data represent the mean ± SEM). (C) Reporter constructs of the PTPN1 promoter were expressed in HEK293T cells, together with control or WT MECP2– or R168X MECP2–expressing plasmids. Expression of of R168X MECP2 (gray), unlike WT MECP2 (black), failed to suppress PTPN1 promoter activity (n = 3, data represent the mean ± SEM). (D) Immunoblots showing PTP1B levels in forebrain lysates obtained from Mecp2–/y and WT male mice; the same lysates were used to blot for MECP2 and the loading control actin. Graph shows quantitation of the immunoblots. All blots are representative of experiments performed 3 times. (E) Immunoblots showing PTP1B levels in forebrain lysates obtained from Mecp2–/+ and WT female mice; the same lysates were used to blot for MECP2 and the loading control actin. Graph shows quantitation of the immunoblots. All blots are representative of experiments performed 3 times. (F) Immunoblots showing PTP1B levels in control and RTT patient–derived fibroblasts; the same lysates were used to blot for the loading control actin. Graph shows quantitation of the immunoblots. All blots are representative of experiments performed 3 times.