Changes of NMDA Receptor Subunit (NR1, NR2B) and Glutamate Transporter (GLT1) mRNA Expression in Huntingtonʼs Disease—An In Situ Hybridization Study

Arzberger, Thomas; Krampfl, K.; Leimgruber, Susanne; Weindl, A.

doi:10.1097/00005072-199704000-00013

Cited by 201 publications

(145 citation statements)

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“…Although previous findings have shown that mutant htt reduces GLT-1 expression in transgenic HD mice (10,22,32) and decreases GLT-1 mRNA and glutamate uptake in the brains of HD patients (33,34), the mechanism underlying this phenomenon has not been revealed.…”

Section: Discussionmentioning

confidence: 89%

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Bradford

Shin

Roberts

et al. 2009

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

328

258

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Huntington disease (HD) is an inherited neurological disorder caused by a polyglutamine expansion in the protein huntingtin and is characterized by selective neurodegeneration that preferentially occurs in striatal medium spiny neurons. Because the medium spiny neurons are innervated abundantly by glutamatergic axons from cortical neurons, the preferential degeneration in the striatal neurons supports the glutamate excitotoxicity theory for HD pathogenesis. Thus, glutamate uptake by glia may be particularly important for preventing glutamate excitotoxicity in HD. Although mutant huntingtin is expressed ubiquitously in various types of cells, it accumulates and forms aggregates in fewer glial cells than in neuronal cells. It remains largely unknown whether and how mutant huntingtin in glia can contribute to the neurological symptoms of HD. We generated transgenic mice that express N-terminal mutant huntingtin in astrocytes, a major type of glial cell that remove extracellular glutamate in the brain. Although transgenic mutant huntingtin in astrocytes is expressed below the endogenous level, it can cause age-dependent neurological phenotypes in transgenic mice. Mice expressing mutant huntingtin show body weight loss, have motor function deficits, and die earlier than wild-type or control transgenic mice. We also found that mutant huntingtin in astrocytes decreases the expression of glutamate transporter by increasing its binding to Sp1 and reducing the association of Sp1 with the promoter of glutamate transporter. These results imply an important role for glial mutant huntingtin in HD pathology and suggest possibilities for treatment.excitotoxicity ͉ glia ͉ neurodegeneration ͉ polyglutamine ͉ glutamate I n Huntington disease (HD), selective neuronal loss occurs preferentially in medium spiny neurons of the striatum and then extends to other brain regions as the disease progresses (1). Because medium spiny neurons are innervated by glutamatergic axons from cortical neurons (2), they are particularly vulnerable to glutamate excitotoxicity, a possible pathogenic mechanism for the preferential neurodegeneration seen in the striatum of HD patients (3). In support of this theory, excitotoxicity of the NMDA receptor, an ionotropic receptor for glutamate, is now associated with HD in various animal models (4, 5).The majority of cells in the brain are glia that support the survival of neuronal cells. Astrocytes are the major type of glia and express glutamate transporters that uptake extracellular glutamate to prevent glutamate neurotoxicity (6-8). Although mutant huntingtin (htt) is expressed in glial cells in the brains of HD mice and patients (9, 10), whether and how mutant htt in glia contributes to neuropathology in vivo remains unknown. Because glial cells can be therapeutic targets, establishing a transgenic mouse model expressing mutant htt specifically in glia can help develop treatment for HD.Current HD mouse models have limitations for studying glial htt contribution, because transgenic htt in these HD mice is e...

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Section: Discussionmentioning

confidence: 89%

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Bradford

Shin

Roberts

et al. 2009

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

328

258

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“…112 Transgenic mice expressing a mutant huntingtin gene show reduced GLT1 mRNA and protein expression but no difference in expression of other glutamate transporters. 113 The decreased mRNA expression was apparent at six weeks and became more pronounced as the animals aged.…”

Section: Hypoxia/ischemiamentioning

confidence: 99%

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Lauriat

McInnes

2007

Mol Psychiatry

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The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and its dysregulation has been associated with multiple psychiatric and neurological disorders. However, investigation of this molecule has been complicated by its complex pattern of alternative splicing, including three coding isoforms and multiple 5 0 -and 3 0 -UTRs that may have a regulatory function. It is likely that these sequences permit modulation of EAAT2 expression with spatial, temporal and or activity-dependent specificity; however, few studies have attempted to delineate the function of these sequences. Additionally, there are problems with the use of antibodies to study protein localization, possibly due to posttranslational modification of critical amino acid residues. This review describes what is currently known about the regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders. EAAT2 has been either primarily or secondarily implicated in a multitude of neuropsychiatric diseases in addition to the normal physiology of learning and memory. Thus, this molecule represents an intriguing therapeutic target once we improve our understanding of how it is regulated under normal conditions.

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“…GLT-1 is the major molecule responsible for the clearing of glutamate from synaptic cleft [157], making it an attractive therapeutic target. Reduced mRNA levels of GLT-1 and decreased glutamate uptake have been described in HD postmortem brains [22] as well as in R6/2 mice [137], suggesting decreased glutamate removal at synapses in HD. Changes in glutamate regulatory system in the presence of mutant huntingtin.…”

Section: Glutamate Transportersmentioning

confidence: 96%

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

Anglada-Huguet¹,

Vidal-Sancho²,

Cabezas-Llobet³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the exon-1 of the huntingtin (htt) gene. The presence of mutant htt (mhtt) results in multiple physiopathological changes, including protein aggregation, transcriptional deregulation, decreased trophic support, alteration in signaling pathways and excitotoxicity. Indeed, the presence of mhtt induces changes in the activities/levels of different kinases, phosphatases and transcription factors that can impact on cell survival. Many studies have provided evidence that transcription may be a major target of mhtt, as gene dysregulation occurs before the onset of symptoms. The greatest number of downregulated genes in HD has led to test the ability of a large number of compounds to restore gene transcription in mouse models of HD. On the other hand, mhtt engenders multiple cellular dysfunctions including an increase of pathological glutamate-mediated excitotoxicity. For that reason, targeting the excess of glutamate has been the goal for many promising drugs leading to clinical trials. Although advances in developing effective therapies are evident, currently, there is no known cure for HD and existing symptomatic treatments are limited.

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Changes of NMDA Receptor Subunit (NR1, NR2B) and Glutamate Transporter (GLT1) mRNA Expression in Huntingtonʼs Disease—An In Situ Hybridization Study

Cited by 201 publications

References 0 publications

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

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