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Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin

The neurodegenerative disorder Huntington disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, resulting in loss of striatal and cortical neurons. Although, the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here, we demonstrate the rel...

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Autores principales: Okamoto, Shu-ichi, Pouladi, Mahmoud A., Talantova, Maria, Yao, Dongdong, Xia, Peng, Ehrnhoefer, Dagmar E., Zaidi, Rameez, Clemente, Arjay, Kaul, Marcus, Graham, Rona K., Zhang, Dongxian, Chen, H.-S. Vincent, Tong, Gary, Hayden, Michael R., Lipton, Stuart A.
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789858/
https://www.ncbi.nlm.nih.gov/pubmed/19915593
http://dx.doi.org/10.1038/nm.2056
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author Okamoto, Shu-ichi
Pouladi, Mahmoud A.
Talantova, Maria
Yao, Dongdong
Xia, Peng
Ehrnhoefer, Dagmar E.
Zaidi, Rameez
Clemente, Arjay
Kaul, Marcus
Graham, Rona K.
Zhang, Dongxian
Chen, H.-S. Vincent
Tong, Gary
Hayden, Michael R.
Lipton, Stuart A.
author_facet Okamoto, Shu-ichi
Pouladi, Mahmoud A.
Talantova, Maria
Yao, Dongdong
Xia, Peng
Ehrnhoefer, Dagmar E.
Zaidi, Rameez
Clemente, Arjay
Kaul, Marcus
Graham, Rona K.
Zhang, Dongxian
Chen, H.-S. Vincent
Tong, Gary
Hayden, Michael R.
Lipton, Stuart A.
author_sort Okamoto, Shu-ichi
collection PubMed
description The neurodegenerative disorder Huntington disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, resulting in loss of striatal and cortical neurons. Although, the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here, we demonstrate the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt), and neuronal survival. Synaptic NMDA receptor (NMDAR) activity induces mtHtt inclusions via a TCP1 ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases vulnerability of mtHtt-neurons to cell death by impairing a neuroprotective CREB—PGC-1α cascade and increasing the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic YAC128 HD mice with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine also blocks synaptic NMDAR activity, decreases neuronal inclusions, and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in HD.
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spelling pubmed-27898582010-06-01 Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin Okamoto, Shu-ichi Pouladi, Mahmoud A. Talantova, Maria Yao, Dongdong Xia, Peng Ehrnhoefer, Dagmar E. Zaidi, Rameez Clemente, Arjay Kaul, Marcus Graham, Rona K. Zhang, Dongxian Chen, H.-S. Vincent Tong, Gary Hayden, Michael R. Lipton, Stuart A. Nat Med Article The neurodegenerative disorder Huntington disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, resulting in loss of striatal and cortical neurons. Although, the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here, we demonstrate the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt), and neuronal survival. Synaptic NMDA receptor (NMDAR) activity induces mtHtt inclusions via a TCP1 ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases vulnerability of mtHtt-neurons to cell death by impairing a neuroprotective CREB—PGC-1α cascade and increasing the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic YAC128 HD mice with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine also blocks synaptic NMDAR activity, decreases neuronal inclusions, and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in HD. 2009-11-15 2009-12 /pmc/articles/PMC2789858/ /pubmed/19915593 http://dx.doi.org/10.1038/nm.2056 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Okamoto, Shu-ichi
Pouladi, Mahmoud A.
Talantova, Maria
Yao, Dongdong
Xia, Peng
Ehrnhoefer, Dagmar E.
Zaidi, Rameez
Clemente, Arjay
Kaul, Marcus
Graham, Rona K.
Zhang, Dongxian
Chen, H.-S. Vincent
Tong, Gary
Hayden, Michael R.
Lipton, Stuart A.
Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title_full Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title_fullStr Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title_full_unstemmed Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title_short Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
title_sort balance between synaptic versus extrasynaptic nmda receptor activity influences inclusions and neurotoxicity of mutant huntingtin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789858/
https://www.ncbi.nlm.nih.gov/pubmed/19915593
http://dx.doi.org/10.1038/nm.2056
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