Dearth of glutamate transporters contributes to striatal excitotoxicity

Brustovetsky, Tatiana; Purl, Kevin J.; Young, Anisa; Shimizu, Kazuyuki; Dubinsky, Janet M.

doi:10.1016/j.expneurol.2004.03.021

Cited by 28 publications

(25 citation statements)

References 63 publications

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“…Although other brain tissues are affected in HD, including cortex (33), the earliest and most dramatic changes are typically observed in the striatum (32). This may be due to physiological differences between striatal and cortical neurons, such as increased susceptibility of striatal neurons to excitotoxicity (34), a process that is thought to lead to ROS production. There is also evidence that mHtt expression in the striatum is sufficient to cause altered expression of oxidative stress genes (35), further indicating that the effects of mHtt expression could be cell type specific.…”

Section: Discussionmentioning

confidence: 99%

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

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

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Oxidative stress plays a key role in late onset diseases including cancer and neurodegenerative diseases such as Huntington disease. Therefore, uncovering regulators of the antioxidant stress responses is important for understanding the course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidative stress response, is deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays a protective role against stress-induced tumorigenesis in mice, but its roles in the antioxidative stress response or its involvement in neurodegeneration have not been investigated. To this end we examined Hace1 WT and KO mice and found that Hace1 KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. Moreover, HACE1 was found to be essential for optimal NRF2 activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. These findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 antioxidative stress response pathway and in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

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

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“…Antisense knockdown of EAAC1 in rats has no effect on the level of extracellular glutamate in the striatum but results in mild neurotoxicity and epilepsy (Rothstein et al, 1996). In vitro, antisense knockdown of EAAC1 also increases the vulnerability of striatal neurons to glutamate toxicity (Brustovetsky et al, 2004).…”

mentioning

confidence: 99%

Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6‐hydroxydopamine‐lesioned rats

Chung

Chen

Chan

et al. 2008

J of Comparative Neurology

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Overactivity of glutamatergic neurotransmission in the basal ganglia is known to be closely related to the onset and pathogenesis of Parkinson's disease. Glutamate homeostasis around glutamatergic synapses is tightly regulated by two groups of glutamate transporters: glial glutamate transporters GLT1 (EAAT2) and GLAST (EAAT1), and neuronal glutamate transporter EAAC1. In order to investigate the changes of glutamate transporters after the onset of Parkinson's disease, unilateral 6-hydroxydopamine-lesioned rat, an animal model of Parkinson's disease, was employed. By immunofluorescence and Western blot analyses, GLT1 and GLAST proteins were significantly reduced in the striatum with lesion. No change in GLT1 and GLAST protein was found in the substantia nigra. The reduction of GLT1 protein in the striatum was more prominent than that of GLAST protein (approximately 40% vs. 20%). In addition, EAAC1 protein was found to be increased in the substantia nigra pars reticulata of the lesioned rats but not in the striatum. The present results indicate that reductions of GLT1 and GLAST may impair glutamate homeostasis around glutamatergic synapses in the striatum and contribute to over-spills of glutamate in the system. An increase in the EAAC1 level in the substantia nigra pars reticulata may increase GABA synthesis and enhance GABAergic neurotransmission. These results indicate that there are differential and distinct modulations of glutamate transporters after dopamine denervation in the 6-hydroxydopamine-lesioned rat.

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“…EAAC1 overexpression decreases NMDA receptor currents (10), and a loss of EAAC1 results in glutamate-induced toxicity in the hippocampus (11). Mice genetically deleted of EAAC1 exhibit increased oxidative stress and age-dependent neurodegeneration, consistent with increased sensitivity to excitotoxic insults over the course of synaptic maturity (79).…”

Section: Discussionmentioning

confidence: 99%

“…EAAC1 has also been linked to pathology in the nervous system. For example, antisense-mediated down-regulation of EAAC1 causes glutamate-induced cell death in the hippocampus (11,12). However, some studies suggest that glutamate transporters contribute to excitotoxicity through transporter reversal during insults such as ischemia (13,14).…”

Section: Metabotropic (Mglur)mentioning

confidence: 99%

N-Methyl-d-aspartate Receptor-dependent Regulation of the Glutamate Transporter Excitatory Amino Acid Carrier 1

Waxman

Baconguis

Lynch

et al. 2007

Journal of Biological Chemistry

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The neuronal transporter excitatory amino acid carrier 1 (EAAC1) is enriched in perisynaptic regions, where it may regulate synaptic spillover of glutamate. In this study we examined potential interactions between EAAC1 and ionotropic glutamate receptors. N-Methyl-D-aspartate (NMDA) receptor subunits NR1, NR2A, and NR2B, but not the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluR2, were co-immunoprecipitated with EAAC1 from neuron-enriched hippocampal cultures. A similar interaction was observed in C6 glioma and human embryonic kidney cells after co-transfection with Myc epitope-tagged EAAC1 and NMDA receptor subunits. Co-transfection of C6 glioma with the combination of NR1 and NR2 subunits dramatically increased (ϳ3-fold) the amount of Myc-EAAC1 that can be labeled with a membrane-impermeable biotinylating reagent. In hippocampal cultures, brief (5 min), robust (100 M NMDA, 10 M glycine) activation of the NMDA receptor decreased biotinylated EAAC1 to ϳ50% of control levels. This effect was inhibited by an NMDA receptor antagonist, intracellular or extracellular calcium chelators, or hypertonic sucrose. Glutamate, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid with cyclothiazide, and thapsigargin mimicked the effects of NMDA. These studies suggest that NMDA receptors interact with EAAC1, facilitate cell surface expression of EAAC1 under basal conditions, and control internalization of EAAC1 upon activation. This NMDA receptor-dependent regulation of EAAC1 provides a novel mechanism that may shape excitatory signaling during synaptic plasticity and/or excitotoxicity.Glutamate is an excitatory amino acid that elicits physiological and excitotoxic responses in the nervous system. Extracellular glutamate is normally maintained at low levels, allowing bursts of glutamate to generate postsynaptic responses during synaptic transmission. Tight regulation of extracellular glutamate is required to allow essential activity and prevent excitotoxicity (for reviews, see Refs. 1-3). Metabotropic (mGluR)3 and ionotropic (AMPA, kainate, and NMDA) receptors mediate the effects of glutamate. mGluRs are G-protein-coupled receptors that activate a variety of second-messenger systems (for review, see Ref. 4), whereas AMPA, kainate, and NMDA receptors are ligand-gated ion channels that also activate intracellular signaling pathways. NMDA receptors have a high affinity for glutamate, are highly permeable to calcium, and do not readily desensitize, all of which contribute to the central role of NMDA receptors in excitotoxicity (5, 6).Removal of extracellular glutamate in the forebrain is controlled by three major excitatory amino acid transporters (EAATs): EAAT1 (GLAST), EAAT2 (GLT-1), and EAAT3 (EAAC1) (for reviews, see Refs. 1 and 7). Glutamate transporters rapidly clear extracellular glutamate, thereby protecting neurons from excitotoxicity (for reviews, see Refs. 1-3). Although GLAST and GLT-1 are mainly glial, EAAC1 is mostly neuronal (8). In area CA1 of the hippocampus, a neuronal transporter li...

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Dearth of glutamate transporters contributes to striatal excitotoxicity

Cited by 28 publications

References 63 publications

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6‐hydroxydopamine‐lesioned rats

N-Methyl-d-aspartate Receptor-dependent Regulation of the Glutamate Transporter Excitatory Amino Acid Carrier 1

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