In Vivo Evidence for NMDA Receptor-Mediated Excitotoxicity in a Murine Genetic Model of Huntington Disease

Chen

Journal of Biological Chemistry

et al. 2013

Background: Oxidative damage has been implicated in the pathology of Huntington disease (HD). Results: Strikingly higher mitochondrial Ca 2ϩ loading and superoxide generation cause significantly higher levels of mitochondrial DNA damage in HD cells. Conclusion: Excessive mitochondrial Ca2ϩ loading-dependent oxidant generation is a causative factor for HD. Significance: Our data reveal new links between dysregulated mitochondrial Ca 2ϩ signaling and elevated oxidative DNA damage in HD.

Section: Discussionmentioning

confidence: 99%

“…Recent results suggest that HTT exp toxicity may also involve disturbed glutamate-induced Ca 2ϩ signaling in MSNs (9,16). It has been reported that HTT exp facilitates activity of NMDA receptors (15,(17)(18)(19)(20)(21) and type 1 inositol 1,4,5-trisphosphate receptors (InsP 3 R1) (22,23), leading to the enhanced intracellular Ca 2ϩ signaling in HD neurons.…”

mentioning

confidence: 99%

Dysregulation of Mitochondrial Calcium Signaling and Superoxide Flashes Cause Mitochondrial Genomic DNA Damage in Huntington Disease

Chen

Journal of Biological Chemistry

et al. 2013

Turkiye Klinikleri J Med Sci

“…Bunu destekler nitelikte, mutant htt ve NR2B içeren NMDAR'lar arasındaki alt üniteye özgün etkileşimlerin nöron ölümüne yol açan mekanizmayı tetiklediği ve Huntington hastalığında nörodejenerasyonun önemli yürütücüleri oldukları ortaya koyulmuştur. 80 …”

Section: N-meti̇l-d-aspartat Reseptörleri̇unclassified

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

Tüfekçi¹,

Tunalı²

2012

201Huntington Hastalığında Toksisite Mekanizmaları ve NMDAR-Aracılı Eksitotoksisitede Poliaminlerin Rolü Ö ÖZ ZE ET T Huntington hastalığı, istemsiz koreik hareketler, bilişsel kayıplar ve psikolojik bozukluklarla karakterize edilen, otozomal dominant geçişli, geç başlangıçlı ve ölümcül bir hastalıktır. Hastalığa sebep olan mutasyon, IT-15 geninin birinci eksonunda tekrar eden CAG bazlarının sayılarındaki artıştır. Mutant genin ifadesi, striyatal gamma aminobütirik asit ileten (GABA-erjik) orta boy dikensi nöronların seçimli ölümüne neden olur. Mutant huntingtin (htt) proteininin konformasyonu, protein yıkımı ve übikütin-proteozom sistemi (UPS), gen yazılımı düzenlemelerin-deki değişimler ve eksitotoksisite, nörodejenerasyonun moleküler mekanizmaları arasındadır. Uyarıcı kimyasalların aşırı miktarı hücreleri sürekli uyararak hassas hücrelerin eksitotoksik ölüm-lerine sebep olurlar. Glutamat da bazal gangliyadan salınan uyarıcı nörotransmiterlerden biridir. Huntington hastalığında striyatal nöronların kaybedilmesi glutamat reseptörü aracılı eksitotoksisitenin patogenezde etkili olabileceğine işaret eder. İyonotrofik glutamat reseptörleri (iGluR) arasın-dan biri olan N-metil-D-Aspartat reseptörleri (NMDAR)'nin uyarılması ve bunu takiben nükleer faktör kappa B (NF ± B) yazılım faktörünün aktivasyonu nöronal ölüm ile sonuçlanır. NMDAR, glutamat bağlanma bölgelerine ek olarak poliamin bağlanma bölgeleri de içerir. Poliaminlerin mutant htt proteininin, NMDAR ve NF ± B yazılım faktörü ile ayrı ayrı ilişki içerisinde olması, bu proteinin, Huntington hastalığında meydana gelen nörodejenerasyonda merkezi bir rol oynayabileceğini düşündürmektedir. Bu nedenle, Huntington hastalığında poliamin metabolizmasının detaylı araştı-rılması ve anlaşılması hastalığın tedavisinde yeni yaklaşımlar üretilmesini sağlayacaktır.A An na ah ht ta ar r K Ke el li im me el le er r: : Huntington hastalığı; NR2A NMDA reseptörü; reseptörler, glutamat; poliaminler A AB BS ST TR RA AC CT T Huntington's Disease is an autosomal dominant, late onset and fatal disorder characterized by involuntary choreic movements, cognitive dysfunction and psychological disturbances. The causative mutation is the expansion of the CAG repeats in the first exon of the IT-15 gene. Mutant gene expression causes selective death of striatal gamma aminobutyric acid releasing (GABA-ergic) medium size spiny neurons. Changes in the conformation of the mutant huntingtin (htt) protein, proteolysis and ubiquitin-proteasome system (UPS), transcriptional disregulation and excitotoxicity are among the molecular mechanisms of neurodegeneration. Excess amounts of excitatory chemicals continuously stimulate the cells and cause excitotoxic death of vulnerable cells. Glutamate is one of the excitatory neurotransmitters released from basal ganglia. The striatal neuron loss in Huntington's Disease points out that glutamate receptor mediated excitotoxicity may play a role in the pathogenesis. Excitation of N-methyl-D-Aspartate receptors (NMDARs), which belong to ionotrophic glutamate recept...

Journal of Biological Chemistry

“…It is the main mediator of brain injury following many acute neurological toxic insults, such as stroke, epileptic seizures, cerebral ischemia, and brain trauma (1,2). It has also been implicated in the pathogenesis of a variety of chronic neurodegenerative disorders (1,3), including Alzheimer (4), Parkinson (5), and Huntington disease (6). However, over-inhibition of NMDAR activity might also result in neuronal death especially in the developing brain, which may call attention to the cautious use of NMDAR blockers such as ketamine in pregnancy or pediatric anesthesia (7)(8)(9).…”

mentioning

confidence: 99%

Switching of N-Methyl-d-aspartate (NMDA) Receptor-favorite Intracellular Signal Pathways from ERK1/2 Protein to p38 Mitogen-activated Protein Kinase Leads to Developmental Changes in NMDA Neurotoxicity

Xiao

Feng

et al. 2011

Excitotoxicity mediated by overactivation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in a variety of neuropathological conditions in the central nervous system (CNS). It has been suggested that N-methyl-D-aspartate (NMDA) neurotoxicity is developmentally regulated, but the definite pattern of the regulation has been controversial, and the underlying mechanism remains largely unknown. Here, we show that NMDA treatment leads to significant cell death in mature (9 and 12 days in vitro) hippocampal neurons or hippocampi of young postnatal day 12 and adult rats but not in immature (3 and 6 days in vitro) neurons or embryonic day 18 and neonatal rat hippocampi. In contrast, NMDA promotes survival of immature neurons against tropic deprivation. Interestingly, it is found that NMDA preferentially activates p38 MAPK in mature neuron and adult rat hippocampus, but it favors ERK1/2 activation in immature neuron and postnatal day 0 rat hippocampus. Moreover, it is shown that NMDA neurotoxicity in mature neuron is mediated via p38 MAPK activation, and neuroprotection in immature neuron is mediated via ERK1/2 activation, whereas all these effects are NR2B-containing NMDAR-dependent, as well as Ca 2؉ -dependent. We also revealed that mature and immature neurons showed no difference in the amplitude of NMDA-induced intracellular calcium ([Ca 2؉ ] i ) increase. However, the basal level of [Ca 2؉ ] i is shown to elevate with the maturation of neuron, and this elevation is attributable to the changes in NMDA neurotoxicity but not to the switch of the NMDAR signaling pathway. Taken together, our results suggest that a switch of NMDA receptor-favorite intracellular signal pathways from ERK1/2 to p38 MAPK and the elevated basal level of [Ca 2؉ ] i with age might be critical for the developmental changes in NMDA neurotoxicity in the hippocampal neuron.