NMDA receptor signaling mediates the expression of protein inhibitor of activated STAT1 (PIAS1) in rat hippocampus

Liu, S.Y.; Ma, Yun‐Li; Lee, Eminy H.Y.

doi:10.1016/j.neuropharm.2012.08.024

Cited by 7 publications

(8 citation statements)

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“…36 This result is also congruent with the finding that PIAS1 expression is regulated by MAPK/ERK-mediated signaling. 27 In addition, we have found that A β also activates Akt, and inhibition of PI-3 K signaling blocked A β induction of PIAS1 expression. These results suggest that A β activation of PI-3 K signaling also mediates neuroprotection against A β toxicity through enhanced PIAS1 expression.…”

Section: Discussionmentioning

confidence: 75%

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Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Tao

Hsu

et al. 2017

Cell Death Differ

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Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD. Cell Death and Differentiation (2017) 24, 597-614; doi:10.1038/cdd.2016.161; published online 10 February 2017The brain of Alzheimer's disease (AD) patient is characterized by the accumulation of senile plaques, and amyloid-β peptides (Aβ 1-40 and Aβ 1-42 ) are the major components of these senile plaques. Aβ is known to cause lipid peroxidation, free radical production, caspase 3 activation and DNA damage that eventually lead to neuronal death. [1][2][3] In addition, the Aβ peptide or overexpression of Aβ causes cognitive impairment in animals. 4,5 This cognitive impairment correlates with amyloid plaque formation 4,6 or precedes it. 7,8 Further, naturally secreted Aβ or the Aβ peptide also inhibits longterm potentiation (LTP) in the hippocampus in vivo and disrupts synaptic and network function. 9,10 More recently, we have found that Aβ induces the expression of activated signal transducer and activator of transcription-1 (STAT1) and Aβ induction of STAT1 mediates the memory-impairing effect of Aβ. 11 On the other hand, it is conceivable that when Aβ produces its toxicity, neurons would develop defense mechanisms to cope with Aβ toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPα is shown to activate neuroprotectin D1 and promote cell survival. 12 In addition, we have found that Aβ activates the MAPK/ERK-SGK (serum-and glucocorticoid-inducible kinase) signaling pathway for neuroprotection against Aβ insult. 13 However, with the role and mechanism of Aβ-induced toxicity been studied extensively, the endogenous protection mechanism induced by Aβ is less well known.Histone acetylation is one kind of epigenetic regulations that has an important role in a wide range of brain functions and disorders, and histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. The HDAC family contains 18 HDAC proteins that belong to different classifications. Inhibitio...

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Section: Discussionmentioning

confidence: 75%

“…27 Here we examined whether A β induction of PIAS1 expression is mediated through A β -induced MAPK/ERK activation. U0126 was used as the inhibitor for MAPK/ERK activation and a sub-threshold concentration of U0126 was used to block A β signaling.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Tao

Hsu

et al. 2017

Cell Death Differ

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“…40 Liu et al identified that PIAS1 has an important role in neuronal plasticity, learning and memory function. 41 Also, CDK2AP1 in the yellow module was recently identified as a susceptibility gene for intellectual disability. 42 Alsayegh et al have also shown that CDK2AP1 gene was associated with the differentiation of human embryonic stem cells and the percentage of cells in the S phase.…”

Section: Discussionmentioning

confidence: 99%

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

et al. 2019

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BackgroundPrevious studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia.MethodThe analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia.ResultsPatients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61–5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only.ConclusionsThe pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

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“…NMDAR activation may activate a kinase cascade that initially phosphorylates Smad3 and allows Smad3/Smad4 complex formation, followed by Smad complex translocation to the nucleus. In addition, we previously showed that both spatial training and NMDAR activation increase PIAS1 expression [ 16 , 32 ]. The presence of increased Smad4 and PIAS1 in the nucleus after training may, therefore, enhance Smad4 SUMOylation.…”

Section: Discussionmentioning

confidence: 99%

Smad4 SUMOylation is essential for memory formation through upregulation of the skeletal myopathy gene TPM2

Hsu

Liu

et al. 2017

BMC Biol

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BackgroundSmad4 is a critical effector of TGF-β signaling that regulates a variety of cellular functions. However, its role in the brain has rarely been studied. Here, we examined the molecular mechanisms underlying the post-translational regulation of Smad4 function by SUMOylation, and its role in spatial memory formation.ResultsIn the hippocampus, Smad4 is SUMOylated by the E3 ligase PIAS1 at Lys-113 and Lys-159. Both spatial training and NMDA injection enhanced Smad4 SUMOylation. Inhibition of Smad4 SUMOylation impaired spatial learning and memory in rats by downregulating TPM2, a gene associated with skeletal myopathies. Similarly, knockdown of TPM2 expression impaired spatial learning and memory, while TPM2 mRNA and protein expression increased after spatial training. Among the TPM2 mutations associated with skeletal myopathies, the TPM2E122K mutation was found to reduce TPM2 expression and impair spatial learning and memory in rats.ConclusionsWe have identified a novel role of Smad4 SUMOylation and TPM2 in learning and memory formation. These results suggest that patients with skeletal myopathies who carry the TPM2E122K mutation may also have deficits in learning and memory functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0452-9) contains supplementary material, which is available to authorized users.

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NMDA receptor signaling mediates the expression of protein inhibitor of activated STAT1 (PIAS1) in rat hippocampus

Cited by 7 publications

References 45 publications

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

Smad4 SUMOylation is essential for memory formation through upregulation of the skeletal myopathy gene TPM2

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