Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism

Fu, Wing‐Yu; Chen, Yu; Şahin, Mustafa; Zhao, Xiaosu; Shi, Lei; Bikoff, Jay B.; Lai, Kwok-On; Yung, Wing‐Ho; Fu, Amy Kit Yu; Greenberg, Michael E.; Ip, Nancy Y.

doi:10.1038/nn1811

Cited by 287 publications

(327 citation statements)

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“…Cdk5 activity is known to regulate the morphogenesis of dendritic spines, the major sites of excitatory synaptic transmission in the CNS, thus influencing the function of neuronal circuits (6,47,48). Under pathological conditions, dendritic spine loss, representing synaptic damage, is known to correlate with the degree of cognitive decline in AD (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

165

182

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The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.C dk5 is a cyclin-dependent kinase that is activated by proteins p35, p25, and p39 (1-3). As a predominantly neuronalspecific kinase, Cdk5 lacks a role in cell-cycle control but has been implicated in an array of neuronal functions, including cell survival, axon guidance, neuronal migration, and regulation of synaptic spine density (4-6). Dysregulation of Cdk5 activity may play a role in the pathogenesis of stroke and several neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease (7-11). Cdk5 is also hyperactivated in response to oxidative stress, mitochondrial dysfunction, excitotoxicity, amyloid-β (Aβ) exposure, calcium overload, and neuroinflammation, thus contributing to neuronal damage. These neurotoxic stimuli activate calpain, which cleaves the Cdk5 activator p35 (or p39) into p25 (or p29); p25 accumulation thus contributes to Cdk5 activation (12-16). These changes trigger various events associated with neurodegeneration. Although increased Cdk5 activity has been observed in AD brains compared with nondemented control brains, the mechanism remains contentious (17).Similarly, nitric oxide (NO) and related species contribute to a number of neurodegenerative diseases. The major source of NO in neurons is neuronal nitric oxide synthase (NOS1). Excitotoxic stress increases intracellular Ca 2+ , which in turn activates NOS1, thus generating NO. In general, NO can stimulate soluble guanylate cyclase to form cGMP or can S-nitrosylate critical cysteine residues to regulate the activity of multiple target proteins, in some sense akin to phosphorylation. Indeed, S-nitrosylation may explain many cGMP-independent mechanisms of NO action in neurodegenerative diseases (18). Our group has demonstrated that NO contributes to neurodegenerative disorders by redox reaction consisting of S-nitrosylation; in some cases this reaction is followed by further oxidation. Proteins affected in this manner include the gelatinase enzyme matrix metalloprotineas...

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Section: Discussionmentioning

confidence: 99%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

165

182

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“…However, contrary to the mechanism of EphB2 receptors, ephrin ligand-mediated activation of EphA4 results in the reduction of synaptic proteins, such as GluR1 and PSD95, and in the retraction and elimination of dendritic spine at excitatory synapses [91,92,105]. Of note, however, EphA4 KO mice also exhibit significant defects in dendritic spines [92].…”

Section: Epha4/ephexin-1mentioning

confidence: 97%

“…The ability to modulate Rho-GTPase activity in neurons is critical during development to regulate neurite outgrowth, growth cone collapse, and axon guidance [87], and, more recently, as regulators of excitatory synapse formation, function, and plasticity in the central nervous system [88]. Indeed, several EphR and ligands localize with postsynaptic density marker PSD95 at excitatory synapses in hippocampal neurons, including EphA4, EphB1, EphB2, and EphB3 [90][91][92][93][94][95]. To date, at least 2 EphRs have been linked to AD.…”

Section: Erythropoietin-producing Hepatocellular Receptor Signalingmentioning

confidence: 99%

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Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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“…EphB enhances synapse development via its interaction with NMDA receptors (13), whereas EphA4, which is mainly expressed in the adult hippocampus, acts as a negative regulator of neurotransmission and hippocampal synaptic plasticity (14). EphA4 activation by its ligands, ephrins, triggers forward signaling (12) that leads to the retraction of dendritic spines via cyclin-dependent kinase 5 (Cdk5)-dependent RhoA activation and reduced cell adhesion (15)(16)(17). EphA4 also causes the removal of synaptic and surface AMPA receptors during homeostatic plasticity (18,19).…”

mentioning

confidence: 99%

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Hung

Huang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a smallmolecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Abeta | receptor tyrosine kinase | ephrin | drug discovery

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Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism

Cited by 287 publications

References 50 publications

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

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