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Cited by 110Genetics and Neurodevelopmental DisordersProtein Tyrosine PhosphatasesNeuroscience and Neuropharmacology Research

PTP1B inhibition suggests a therapeutic strategy for Rett syndrome

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Krishnan, Navasona, Krishnan, Keerthi, Connors, Christopher R., Choy, Meng S., Page, Rebecca, Peti, Wolfgang, Van Aelst, Linda, Shea, Stephen D. +1 more·2015·Journal of Clinical Investigation
DOI 10.1172/jci80323PMC PMC4563751
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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.

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  • Treatment of Mecp2 null mice with a PTP1B antagonist extended lifespan, decreased hindlimb clasping and improved motor performance.

    “For example, the treatment of Mecp2 null mice with a protein-tyrosine phosphatase 1B (PTP1B) antagonist that was developed to treat Type II diabetes extended lifespan, decreased hindlimb clasping and improved motor performance [207].”

    From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [207]

    The Results section, “Inhibition of PTP1B improved survival in Mecp2 -/y mice” (page not provided), reports extended survival in male Mecp2-null mice. The paw-clasping and rotarod passages (“Volume 125 Number 8 August 2015,” page not provided) report those improvements in heterozygous female Mecp2 -/+ mice, not null mice. The cited passages also do not establish that the inhibitor was developed to treat type II diabetes. (LLM, conf=0.92)

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Cited by

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Authors
Krishnan, N., Krishnan, K., Connors, C. R., Choy, M. S., Page, R., Peti, W., Van Aelst, L., Shea, S. D., & Tonks, N. K.
Affiliations
  • Cold Spring Harbor Laboratory (US)
  • Brown University (US)
Corresponding author
Tonks, Nicholas K.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2015-07-27
Volume
125
Issue
8
Pages
3163-3177
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci80323
PMC
PMC4563751
OpenAlex
W2127922280
Cited by
110
References
6
Citations by year
2026: 7 · 2025: 4 · 2024: 6 · 2023: 15 · 2022: 4 · 2021: 14 · 2020: 13 · 2019: 18 · 2018: 7 · 2017: 14 · 2016: 7 · 2015: 1
FWCI
6.87
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • American Diabetes Association (1-14-ACN-31)
  • Brown University
  • Cold Spring Harbor Laboratory (CA45508)
  • National Institutes of Health (CA45508, CA53840, 5p30ca045508-35)
  • National Institute of Mental Health (R01MH082808, MH082808)
  • National Cancer Institute (P30-CA045508, CA45508, R37CA053840, R01CA053840, CA53840)
  • National Institute of General Medical Sciences (GM55989, R01GM055989)
  • National Institute of Neurological Disorders and Stroke (R01NS082266)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Rett syndrome, PTP1B, MeCP2, protein tyrosine phosphatase inhibition, TrkB, BDNF signaling, tyrosine phosphorylation, Mecp2 knockout mice, autism spectrum disorder, therapeutic target
MeSH terms
Animals, Disease Models, Animal, Enzyme Inhibitors, Female, Male, Mice, Inbred CBA, Mice, Mutant Strains, Phosphorylation, Signal Transduction, Rett Syndrome, Brain-Derived Neurotrophic Factor, Receptor, trkB, Mice, Methyl-CpG-Binding Protein 2, Protein Tyrosine Phosphatase, Non-Receptor Type 1

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