ArticleNature medicine2009
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.
Article in Nature medicine, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 236 papers.
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Who cites it
236 citing papers in PubMed, 427 citations in OpenAlex.
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- Long term administration of selective NMDA GluN2B receptor blocker Ro25-6981 attenuates neurodegeneration in mouse model of spinocerebellar ataxia type 1 (SCA1).Cell death discovery · 2026Article
- Targeting Glutamate Excitotoxicity With Memantine Modulates Glial Response and Protects Motoneurons After Spinal Root Lesion.Journal of neurochemistry · 2026Article
- Huntingtin and its allies at the cortico-striatal synapse.Cell death & disease · 2026Review
- Membrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spread.Science advances · 2026Article
- Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.Communications biology · 2025Article
- Exploring NMDAR pathways in ischemic stroke: implications for neurotoxic and neuroprotective mechanisms and therapeutic strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- AI-Enhanced Transcriptomic Discovery of Druggable Targets and Repurposed Therapies for Huntington's Disease.Brain sciences · 2025Review
- Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.Antioxidants (Basel, Switzerland) · 2025Review
- Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids.Molecular psychiatry · 2025Article
- AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders.Translational neurodegeneration · 2025Review
- Altered GABAergic Homeostasis in the Striatum of Dopamine Transporter Knockout Rats.Current neuropharmacology · 2025Article
- Calcium Signalling in Neurological Disorders, with Insights from Miniature Fluorescence Microscopy.Cells · 2024Review
- Unraveling the Prefrontal Cortex-Basolateral Amygdala Pathway's Role on Schizophrenia's Cognitive Impairments: A Multimodal Study in Patients and Mouse Models.Schizophrenia bulletin · 2024Article
- Review
- Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases.Nature reviews. Neuroscience · 2024Review
- Neurodegenerative Diseases: New Hopes and Perspectives.Current molecular medicine · 2024Review
- Curbing Rhes Actions: Mechanism-based Molecular Target for Huntington's Disease and Tauopathies.CNS & neurological disorders drug targets · 2024Review
176 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.