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Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin
Open accessAbstract
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-γ coactivator-1α (PGC-1α) 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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Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., & Finkbeiner, S. (2004) · Nature · doi:10.1038/nature02998 · Cited by 1,979
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002) · Nature Neuroscience · doi:10.1038/nn835 · Cited by 1,686
Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond
Lipton, S. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1958 · Cited by 909
Self-citationFibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches
Tsai, J., Grutzendler, J., Duff, K., & Gan, W.-B. (2004) · Nature Neuroscience · doi:10.1038/nn1335 · Cited by 561
Therapeutic Effects of Coenzyme Q10and Remacemide in Transgenic Mouse Models of Huntington's Disease
Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Ferrante, K. L., Jenkins, B. G., Hersch, S. M., & Beal, M. F. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01592.2002 · Cited by 391
PGC-1α, a New Therapeutic Target in Huntington's Disease?
McGill, J. K., & Beal, M. F. (2006) · Cell · doi:10.1016/j.cell.2006.10.023 · Cited by 131
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Ross, C. A., & Tabrizi, S. J. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70245-3 · Cited by 1,743
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644
Excitotoxicity and stroke: Identifying novel targets for neuroprotection
Lai, T. W., Zhang, S., & Wang, Y. T. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.11.006 · Cited by 1,106
Excitotoxicity: Bridge to various triggers in neurodegenerative disorders
Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R., & Sharma, P. L. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.10.032 · Cited by 665
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Vécsei, L., Szalárdy, L., Fülöp, F., & Toldi, J. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3793 · Cited by 641
Pathogenic mechanisms following ischemic stroke
Khoshnam, S. E., Winlow, W., Farzaneh, M., Farbood, Y., & Moghaddam, H. F. (2017) · Neurological Sciences · doi:10.1007/s10072-017-2938-1 · Cited by 621
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Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M. W., Okamoto, S.-I., Dziewczapolski, G., Nakamura, T., Cao, G., Pratt, A. E., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306832110 · Cited by 600
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Fu, H., Hardy, J., & Duff, K. E. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0221-2 · Cited by 585
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Parsons, M. P., & Raymond, L. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.03.030 · Cited by 553
Milnerwood, A. J., Gladding, C. M., Pouladi, M. A., Kaufman, A. M., Hines, R. M., Boyd, J. D., Ko, R. W. Y., Vasuta, O. C., Graham, R. K., Hayden, M. R., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.008 · Cited by 517
Self-citationHuntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies
Jimenez-Sanchez, M., Licitra, F., Underwood, B. R., & Rubinsztein, D. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024240 · Cited by 507
Danysz, W., & Parsons, C. G. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02057.x · Cited by 500
Xia, P., Chen, H.-S. V., Zhang, D., & Lipton, S. A. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2488-10.2010 · Cited by 379
Self-citationNuclear calcium signalling in the regulation of brain function
Bading, H. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3531 · Cited by 373
Choosing an animal model for the study of Huntington's disease
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Wu, Q. J., & Tymianski, M. (2018) · Molecular Brain · doi:10.1186/s13041-018-0357-8 · Cited by 319
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Finkbeiner, S. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007476 · Cited by 255
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Plotkin, J. L., Day, M., Peterson, J. D., Xie, Z., Kress, G. J., Rafalovich, I., Kondapalli, J., Gertler, T. S., Flajolet, M., Greengard, P., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.032 · Cited by 187
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Uddin, M. S., Rahman, M. M., Jakaria, M., Rahman, M. S., Hossain, M. S., Islam, A., Ahmed, M., Mathew, B., Omar, U. M., Barreto, G. E., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01911-8 · Cited by 156
Cholesterol metabolism in Huntington disease
Karasinska, J. M., & Hayden, M. R. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.132 · Cited by 154
Self-citationMechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities
Macrez, R., Stys, P. K., Vivien, D., Lipton, S. A., & Docagne, F. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30165-x · Cited by 127
Self-citation(2018) · doi:10.1038/s41467-018-06675-3 · Cited by 111
Trudler, D., Sanz-Blasco, S., Eisele, Y. S., Ghatak, S., Bodhinathan, K., Akhtar, M. W., Lynch, W. P., Piña-Crespo, J. C., Talantova, M., Kelly, J. W., et al. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-20.2020 · Cited by 104
Self-citationWills, T. A., Klug, J. R., Silberman, Y., Baucum, A. J., Weitlauf, C., Colbran, R. J., Delpire, E., & Winder, D. G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113820109 · Cited by 98
Barron, J. C., Hurley, E. P., & Parsons, M. P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.689332 · Cited by 85
Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion
Sharma, M., & Subramaniam, S. (2019) · Journal of Cell Biology · doi:10.1083/jcb.201807068 · Cited by 76
The influence of synaptic activity on neuronal health
Bell, K. F., & Hardingham, G. E. (2011) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.01.002 · Cited by 77
Fleming, T. M., Scott, V., Naskar, K., Joe, N., Brown, C. H., & Stern, J. E. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.207340 · Cited by 73
Koeglsperger, T., Li, S., Brenneis, C., Saulnier, J. L., Mayo, L., Carrier, Y., Selkoe, D. J., & Weiner, H. L. (2013) · Glia · doi:10.1002/glia.22490 · Cited by 73
Povysheva, N. V., & Johnson, J. W. (2012) · Journal of Neurophysiology · doi:10.1152/jn.01017.2011 · Cited by 62
Stazi, M., & Wirths, O. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02120-z · Cited by 59
Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease
Galvan, L., André, V. M., Wang, E. A., Cepeda, C., & Levine, M. S. (2012) · Journal of Huntington's Disease · doi:10.3233/jhd-2012-120009 · Cited by 56
Axonopathy in Huntington's disease
Li, J.-Y., & Conforti, L. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.08.010 · Cited by 55
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Wang, Z.-C., Zhao, J., & Li, S. (2013) · Neuroscience Bulletin · doi:10.1007/s12264-013-1383-2 · Cited by 54
Lloret, A., & Beal, M. F. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02809-1 · Cited by 52
Faster perceptual learning through excitotoxic neurodegeneration
Beste, C., Wascher, E., Dinse, H. R., & Saft, C. (2012) · Current Biology · doi:10.1016/j.cub.2012.08.012 · Cited by 33
Metadata
- Authors
- Okamoto, S.-I., Pouladi, M. A., Talantova, M., Yao, D., Xia, P., Ehrnhoefer, D. E., Zaidi, R., Clemente, A., Kaul, M., Graham, R. K., Zhang, D., Vincent Chen, H.-S., Tong, G., Hayden, M. R., & Lipton, S. A.
- Venue
- Nature Medicine
- Published
- 2009-11-15
- Volume
- 15
- Issue
- 12
- Pages
- 1407-1413
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2027275070
- Cited by
- 436
- References
- 7
- FWCI
- 17.19
- Type
- journal article
- Language
- en
- Open access
- green
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