Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

Gascón, Sergio; Sobrado, Mónica; Roda, J.M.; Rodrı́guez-Peña, Angeles; Dı́az-Guerra, Margarita

doi:10.1038/sj.mp.4002017

Cited by 109 publications

(108 citation statements)

References 49 publications

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“…The synapsin-I present in synaptic vesicles, plays a wide range of neuronal functions including neurotransmitter release, synaptogenesis, cytoskeletal structural dynamics, energy metabolism, ion homeostasis, and protein folding [51,52]. PSD-95 interacts with N-methyl-Daspartate receptors [53] and are implicated in various important roles in the regulation of ionchannel function, neuronal differentiation, synaptogenesis, synaptic plasticity, and the processes of learning and memory [54,55]. PSD-95 could target membrane addition to polarized synaptic compartments, formation of cellular junctions as well as synaptic protein anchoring and trafficking [56].…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

Ansari

Roberts

Scheff

2008

Free Radical Biology and Medicine

277

220

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Oxidative stress, an imbalance between oxidants and antioxidants, contributes to the pathogenesis of traumatic brain injury (TBI). Oxidative neurodegeneration is a key mediator of exacerbated morphological responses and deficits in behavioral recoveries. The present study assessed early hippocampal sequential imbalance to possibly enhance antioxidant therapy. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate cortical contusion. At various times post TBI, animals were killed and the hippocampus analyzed for antioxidants (GSH, GSSG, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and catalase), and oxidants (acrolein,, protein carbonyl [PC] and 3-nitrotyrosine. Synaptic markers (synapsin-I, post synaptic density-95 [PSD-95], synapse associated protein-97 [SAP-97], growth associated protein-43 were also analyzed. All values were compared to sham operated animals. Significant time-dependent changes in antioxidants were observed as early as 3 h post trauma and paralleled increases in oxidants (4-HNE, acrolein and PC) with peak values obtained at 24-48 h. Time dependent changes in synaptic proteins (synapsin-I, PSD-95 and SAP-97) occurred well after levels of oxidants peaked. These results indicate that depletion of antioxidant systems following trauma could adversely affect synaptic function and plasticity. Early onset of oxidative stress suggests that the initial therapeutic window following TBI appears to be relatively short and it may be necessary to stagger selective types of anti-oxidant therapy to target specific oxidative components.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

Ansari

Roberts

Scheff

2008

Free Radical Biology and Medicine

277

220

View full text Add to dashboard Cite

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“…The truncated form of the transporter was highly stable, being present in cultured hippocampal neurons 24 h after the excitotoxic insult. In addition to VGAT, calpains cleave other proteins in brain ischemia and under excitotoxic conditions, giving rise to stable cleavage products (Chan and Mattson, 1999;Hou et al, 2006;Cao et al, 2007;Xu et al, 2007;Bevers and Neumar, 2008;Gascó n et al, 2008). Excitotoxic stimulation also decreased the mRNA for VGAT, which may prevent de novo synthesis of the transporter to compensate for the loss of the full-length protein in surviving neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Under normal physiological conditions the activation of calpains is tightly regulated and plays a key role in the cleavage of selected protein targets (Liu et al, 2008). Activation of these proteases due to a [Ca 2ϩ ] i overload under excitotoxic conditions cleaves key synaptic proteins in glutamatergic synapses, including ionotropic (AMPA and NMDA receptor subunits) and metabotropic glutamate receptors (Xu et al, 2007;Yuen et al, 2007;Gascó n et al, 2008), and postsynaptic scaffold proteins (Jourdi et al, 2005), but little information is available regarding the effect of calpains on GABAergic synapses. In the present study we evaluated the changes in VGAT protein levels and cellular distribution in pathological conditions, including excitotoxicity, brain ischemia, and following status epilepticus.…”

Section: Introductionmentioning

confidence: 99%

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Gomes¹,

Lobo²,

Melo³

et al. 2011

J. Neurosci.

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GABA is the major inhibitory neurotransmitter in the CNS and changes in GABAergic neurotransmission affect the overall activity of neuronal networks. The uptake of GABA into synaptic vesicles is mediated by the vesicular GABA transporter (VGAT), and changes in the expression of the transporter directly regulate neurotransmitter release. In this work we investigated the changes in VGAT protein levels during ischemia and in excitotoxic conditions, which may affect the demise process. We found that VGAT is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, giving rise to a stable truncated cleavage product (tVGAT). VGAT cleavage was also observed after transient middle cerebral artery occlusion in mice, a cerebral ischemia model, and following intrahippocampal injection of kainate, but no effect was observed in transgenic mice overexpressing calpastatin, a calpain inhibitor. Incubation of isolated cerebrocortical synaptic vesicles with recombinant calpain also induced the cleavage of VGAT and formation of stable tVGAT. Immunoblot experiments using antibodies targeting different regions of VGAT and N-terminal sequencing analysis showed that calpain cleaves the transporter in the N-terminal region, at amino acids 52 and 60. Immunocytochemistry of GABAergic striatal neurons expressing GFP fusion proteins with the full-length VGAT or tVGAT showed that cleavage of the transporter induces a loss of synaptic delivery, leading to a homogeneous distribution of the protein along neurites. Our results show that excitotoxicity downregulates full-length VGAT, with a concomitant generation of tVGAT, which is likely to affect GABAergic neurotransmission and may influence cell death during ischemia.

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“…Mislocalization of NMDAR to the peri-and extra-synaptic membrane (non-postsynaptic density fraction) in pre-symptomatic YAC128 striatum leads to a loss of neuroprotection mechanisms and an increase in activity of cell death pathways [58,152,153]. In parallel, excitotoxicity triggered by overactivation of NR2B-containing NMDARs results in rapid dissociation of synaptic NMDARs from the postsynaptic scaffolding complex and downstream survival signaling [154]. Thus, 1 possible scenario is that excitotoxic damage occurs in striatal MSNs in the early stage of the disease by dysregulation of NMDAR-linked signaling pathways, which then leads to a cascade of age-dependent pathophysiological events.…”

Section: Excitotoxicitymentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

Cited by 109 publications

References 49 publications

Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

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