Inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity reverses behavioral deficits in a rodent model of autism

Chatterjee, Manavi; Singh, Prati Pal; Xu, Jian; Lombroso, Paul J.; Kurup, Pradeep

doi:10.1016/j.bbr.2020.112713

Cited by 6 publications

(3 citation statements)

References 55 publications

(63 reference statements)

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“…It is noteworthy that a significant decline of H 2 S levels has been observed in AD patients, suggesting that the use of H 2 S donors is a promising strategy for the treatment of neurodegenerative diseases [40]. Indeed, the effects of short-term exposure to TC-2153 represent positive results in a transgenic model of AD, depressive disorders [9], and autism [41]. However, it should be noted that not only oxidative but also reductive stress such as excess of the H2S takes place in the cell and may lead to adverse effects [42].…”

Section: Discussionmentioning

confidence: 99%

Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable. After unsuccessful attempts to create drugs targeting the amyloid-β pathway, a search for alternative approaches and treatments targeting nonamyloid AD pathologies is currently underway. One of them is inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity, which is increased in the prefrontal cortex of AD patients. Here we examined effects of prolonged treatment of OXYS rats which mimic key signs of sporadic AD with a STEP inhibitor, TC-2153, on the progression of signs of AD. TC-2153 had an ambiguous effect on the behavior of the animals: it significantly reduced the already low locomotor and exploratory activities and enhanced anxiety-related behavior in OXYS rats but improved their long-term memory in the Morris water maze. Moreover, TC-2153 had no effect on the accumulation of the amyloid-β protein and on the STEP61 protein level; the latter in the cortex and hippocampus did not differ between OXYS rats and control Wistar rats. These results suggest that the effects of prolonged treatment with TC-2153 may be mediated by mechanisms not related to STEP. In particular, TC-2153 can act as a potential hydrogen sulfide donor and thus substantially affect redox homeostasis.

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Section: Discussionmentioning

confidence: 99%

Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer’s Disease

et al. 2021

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“…Ptk2b (−1.7) (Pyk2) is a non-receptor cell-adhesion kinase and scaffold protein which, if either overexpressed or knocked down, impairs cortical neuron migration by altering growth cone dynamics (Fan et al, 2018). Ptk2b is regulated by Ptpn5 (−1.5) (STEP), a tyrosine phosphatase (Chatterjee et al, 2020). None of these three genes has been linked to autism in GWAS but downregulation of Ptk2b, Ptpn5 and/or Mllt11a by VPA has the potential to alter neuronal migration at a critical time when circuits are forming in the fetal brain.…”

Section: Examination Of Tablesmentioning

confidence: 99%

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Dorsey

Mocci

Lane

et al. 2023

Preprint

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There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy, moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNAseq data ob-tained from fetal mouse brains 3 hr after VPA administration revealed that VPA significantly [p(FDR) ≤ 0.025] increased or decreased the expression of approximately 7,300 genes. No significant sex dif-ferences in VPA-induced gene expression were observed. Expression of genes associated with neurodevelopmental disorders such as autism as well as neurogenesis, axon growth and synapto-genesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 400 autism risk genes was significantly altered by VPA. In addition, expression of 247 genes that have been reported to play fundamental roles in the development of the nervous system, but are not linked to autism by GWAS, was significantly increased or decreased by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria provides potential targets for future hypothesis-driven approaches to elucidating the proximal underlying causes of defective brain connectivity in neuro-developmental disorders such as autism.

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“…STEP (STriatal-Enriched protein tyrosine Phosphatase) is a PTP expressed in the brain, involved in motor control and cognition. STEP is a validated drug target for neurological disorders including Alzheimer's and Parkinson's disease, with both genetic and pharmacological inhibition of STEP shown to improve cognitive function and hippocampal memory [2,3]. Seven crystal structures of human STEP plus one of mouse STEP are currently available from the Protein Data Bank [4,5], two of which have bound allosteric small-molecule activators [6].…”

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confidence: 99%

Uncovering new ligandable sites in STEP (striatal-enriched protein tyrosine phosphatase)

Guerrero,

Riley,

Keedy

2023

Acta Cryst Sect A

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PTPs (protein tyrosine phosphatases) are a family of enzymes heavily involved in cell signalling pathways, the dysregulation of which has been implicated in numerous diseases [1]. STEP (STriatal-Enriched protein tyrosine Phosphatase) is a PTP expressed in the brain, involved in motor control and cognition. STEP is a validated drug target for neurological disorders including Alzheimer's and Parkinson's disease, with both genetic and pharmacological inhibition of STEP shown to improve cognitive function and hippocampal memory [2,3]. Seven crystal structures of human STEP plus one of mouse STEP are currently available from the Protein Data Bank [4,5], two of which have bound allosteric small-molecule activators [6]. However, much remains to be discovered about the ligandability and potential for allostery at various sites in STEP, which would have tremendous implications for drug design to combat neurological diseases. In this work, we soaked STEP crystals with a variety of ligands, including smallmolecule inhibitors previously shown to covalently target the conserved active-site Cys residue and block catalytic activity in other PTP family members, but untested with STEP [7,8]. The resulting high-resolution X-ray diffraction datasets and crystal structures reveal that, surprisingly, these inhibitors target a novel site involving a covalent bond to a different surface Cys that is unique to KIM-type PTPs such as STEP. Moreover, in other soaked structures, we observe a serendipitously bound endogenous metabolite under the catalytic WPD loop in the active site, whose biological relevance is not yet clear. Overall, our findings may have implications for uncovering previously unknown allosteric pathways and regulatory mechanisms in STEP.

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Inhibition of striatal-enriched protein tyrosine phosphatase (STEP) activity reverses behavioral deficits in a rodent model of autism

Cited by 6 publications

References 55 publications

Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer’s Disease

Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer’s Disease

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

Uncovering new ligandable sites in STEP (striatal-enriched protein tyrosine phosphatase)

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