Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity
Open accessAbstract
Huntington’s disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N -methyl- d -aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
R6/2 mice show pronounced striatal atrophy resembling that in humans.
“R6/2 mice display marked striatal atrophy (Hansson et al. , 1999; Li et al. , 2005) similar to humans”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Hansson et al., 1999
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
The Bcl-2 Protein Family: Arbiters of Cell Survival
Adams, J. M., & Cory, S. (1998) · Science · doi:10.1126/science.281.5381.1322 · Cited by 5,303 · see citing works
Oxidative Stress, Glutamate, and Neurodegenerative Disorders
Coyle, J. T., & Puttfarcken, P. (1993) · Science · doi:10.1126/science.7901908 · Cited by 3,762 · see citing works
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S. W., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81369-0 · Cited by 3,073 · see citing works
West, M. J., Slomianka, L., & Gundersen, H. J. G. (1991) · The Anatomical Record · doi:10.1002/ar.1092310411 · Cited by 2,994 · see citing works
Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J., & D, N. A. M. (1997) · Science · doi:10.1126/science.277.5334.1990 · Cited by 2,849 · see citing works
Neuropathological Classification of Huntingtonʼs Disease
Vonsattel, J., Myers, R. H., STEVENS, T. J., Ferrante, R. J., Bird, E. D., & Richardson, E. P. (1985) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-198511000-00003 · Cited by 2,598 · see citing works
Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L., & Bates, G. P. (1997) · Cell · doi:10.1016/s0092-8674(00)80513-9 · Cited by 2,188 · see citing works
Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80514-0 · Cited by 1,291 · see citing works
Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid
Beal, M. F., Kowall, N. W., Ellison, D. W., Mazurek, M. F., Swartz, K. J., & Martin, J. B. (1986) · Nature · doi:10.1038/321168a0 · Cited by 1,287 · see citing works
Quinolinic Acid: An Endogenous Metabolite That Produces Axon-Sparing Lesions in Rat Brain
Schwarcz, R. M., Whetsell, W. O., & Mangano, R. M. (1983) · Science · doi:10.1126/science.6849138 · Cited by 1,269 · see citing works
Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea
Coyle, J. T., & Schwarcz, R. M. (1976) · Nature · doi:10.1038/263244a0 · Cited by 1,255 · see citing works
Differential loss of striatal projection neurons in Huntington disease.
Reiner, A. J., Albin, R. L., Anderson, K. D., D’Amato, C. J., Penney, J. B., & Young, A. B. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.15.5733 · Cited by 999 · see citing works
Schmued, L. C., Albertson, C., & Slikker, W. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01387-x · Cited by 995 · see citing works
McGeer, E. G., & McGeer, P. L. (1976) · Nature · doi:10.1038/263517a0 · Cited by 836 · see citing works
Hsp70 exerts its anti‐apoptotic function downstream of caspase‐3‐like proteases
Jäättelä, M., Wissing, D., Kokholm, K., Kallunki, T., & Egeblad, M. (1998) · The EMBO Journal · doi:10.1093/emboj/17.21.6124 · Cited by 679 · see citing works
Trottier, Y., Lutz, Y., Stévanin, G., Imbert, G., Devys, D., Cancel‐Tassin, G., Saudou, F., Weber, C., David, G., Tora, L., et al. (1995) · Nature · doi:10.1038/378403a0 · Cited by 654 · see citing works
Paoletti, F., Aldinucci, D., Mocali, A., & Caparrini, A. (1986) · Analytical Biochemistry · doi:10.1016/0003-2697(86)90026-6 · Cited by 637 · see citing works
Graveland, G. A., Williams, R. S., & DiFiglia, M. (1985) · Science · doi:10.1126/science.3155875 · Cited by 612 · see citing works
Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models
Portera‐Cailliau, C., Hedreen, J. C., Price, D., & Koliatsos, V. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-05-03775.1995 · Cited by 607 · see citing works
A huntingtin-associated protein enriched in brain with implications for pathology
Li, X., Li, S.-H., Sharp, A. H., Nucifora, F. C., Schilling, G., Lanahan, A. A., Worley, P. F., Snyder, S. H., & Ross, C. A. (1995) · Nature · doi:10.1038/378398a0 · Cited by 605 · see citing works
Stipe, J., White, D., & Arsdale, E. V. (1979) · AJN American Journal of Nursing · doi:10.2307/3424618 · Cited by 602 · see citing works
Alternative excitotoxic hypotheses
Albin, R. L., & Greenamyre, J. T. (1992) · Neurology · doi:10.1212/wnl.42.4.733 · Cited by 574 · see citing works
Neurotrophins and brain insults
Lindvall, O., Kokaia, Z., Bengzon, J., Elmér, E., & Kokaia, M. (1994) · Trends in Neurosciences · doi:10.1016/0166-2236(94)90139-2 · Cited by 558 · see citing works
Widespread expression of Huntington's disease gene (IT15) protein product
Sharp, A. H., Loev, S. J., Schilling, G., Li, S.-H., Li, X.-J., Bao, J., Wagster, M. V., Kotzuk, J. A., Steiner, J. P., Lo, A., et al. (1995) · Neuron · doi:10.1016/0896-6273(95)90345-3 · Cited by 513 · see citing works
Cha, J.-H. J., Kosinski, C. M., Kerner, J. A., Alsdorf, S. A., Mangiarini, L., Davies, S. W., Penney, J. B., Bates, G. P., & Young, A. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6480 · Cited by 504 · see citing works
Chronic quinolinic acid lesions in rats closely resemble Huntington's disease
Beal, M. F., Ferrante, R. J., Swartz, K., & Kowall, N. W. (1991) · Journal of Neuroscience · doi:10.1523/jneurosci.11-06-01649.1991 · Cited by 499 · see citing works
Excitotoxic injury of the neostriatum: a model for Huntington's disease
DiFiglia, M. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90111-m · Cited by 474 · see citing works
Trottier, Y., Devys, D., Imbert, G., Saudou, F., Gourfinkel‐An, I., Lutz, Y., Weber, C., Agid, Y., Hirsch, É. C., & Mandel, J. (1995) · Nature Genetics · doi:10.1038/ng0595-104 · Cited by 452 · see citing works
[2] Citrate synthase from rat liver
Shepherd, D., & Garland, P. B. (1969) · Methods in Enzymology · doi:10.1016/0076-6879(69)13006-2 · Cited by 434 · see citing works
Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH
Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y., Myers, R., Roses, A. D., Vance, J. M., & Strittmatter, W. J. (1996) · Nature Medicine · doi:10.1038/nm0396-347 · Cited by 430 · see citing works
Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues
Strong, T. V., Tagle, D. A., Valdes, J. M., Elmer, L. W., Boehm, K., Swaroop, M., Kaatz, K. W., Collins, F. S., & Albin, R. L. (1993) · Nature Genetics · doi:10.1038/ng1193-259 · Cited by 417 · see citing works
NMDA Receptor Losses in Putamen from Patients with Huntington's Disease
Young, A. B., Greenamyre, J. T., Hollingsworth, Z. R., Albin, R. L., D’Amato, C. J., Shoulson, I., & Penney, J. B. (1988) · Science · doi:10.1126/science.2841762 · Cited by 394 · see citing works
Kalchman, M. A., Koide, H., McCutcheon, K. M., Graham, R. K., Nichol, K., Nishiyama, K., Kazemi‐Esfarjani, P., Lynn, F. C., Wellington, C. L., Metzler, M., et al. (1997) · Nature Genetics · doi:10.1038/ng0597-44 · Cited by 378 · see citing works
Early Loss of Neostriatal Striosome Neurons in Huntingtonʼs Disease
Hedreen, J. C., & Folstein, S. E. (1995) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199501000-00013 · Cited by 327 · see citing works
Ferrante, R., Kowall, N., & Richardson, E. (1991) · The Journal of Neuroscience · doi:10.1523/jneurosci.11-12-03877.1991 · Cited by 306 · see citing works
Gutekunst, C., Levey, A. I., Heilman, C. J., Whaley, W. L., Yi, H. L., Nash, N. R., Rees, H. D., Madden, J. J., & Hersch, S. M. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.19.8710 · Cited by 305 · see citing works
Ischemic tolerance in the brain
Chen, J., & Simon, R. P. (1997) · Neurology · doi:10.1212/wnl.48.2.306 · Cited by 272 · see citing works
Ferrante, R. J., Kowall, N. W., Cipolloni, P. B., Storey, E., & Beal, M. F. (1993) · Experimental Neurology · doi:10.1006/exnr.1993.1006 · Cited by 244 · see citing works
Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.
Hurlbert, M. S., Zhou, W., Wasmeier, C., Kaddis, F. G., Hutton, J. C., & Freed, C. R. (1999) · Diabetes · doi:10.2337/diabetes.48.3.649 · Cited by 218 · see citing works
Mitochondrial Control of Acute Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells
Castilho, R. F., Hansson, O., Ward, M. W., Budd, S. L., & Nicholls, D. G. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-24-10277.1998 · Cited by 197 · see citing works
Self-citationMarini, A. M., & Paul, S. M. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.14.6555 · Cited by 166 · see citing works
Bao, J., Sharp, A. H., Wagster, M. V., Bêcher, M. W., Schilling, G., Ross, C. A., Dawson, V. L., & Dawson, T. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.10.5037 · Cited by 158 · see citing works
Neurobiology of Huntington's Disease
Sharp, A. H., & Ross, C. A. (1996) · Neurobiology of Disease · doi:10.1006/nbdi.1996.0002 · Cited by 138 · see citing works
Role of excitotoxicity in human neurological disease
Beal, M. F. (1992) · Current Opinion in Neurobiology · doi:10.1016/0959-4388(92)90035-j · Cited by 114 · see citing works
Huntington's disease: translating a CAG repeat into a pathogenic mechanism
MacDonald, M. E., & Gusella, J. F. (1996) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(96)80097-3 · Cited by 96 · see citing works
Increased Vulnerability to 3‐Nitropropionic Acid in an Animal Model of Huntington's Disease
Bogdanov, M. B., Ferrante, R. J., Kuemmerle, S., Klivènyi, P., & Beal, M. F. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71062642.x · Cited by 90 · see citing works
Huang, Q. M., Zhou, D., Sapp, E., et al. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00494-p · Cited by 68 · see citing works
Meier, T. J., Ho, D. Y., & Sapolsky, R. M. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69031039.x · Cited by 65 · see citing works
Schwartz, P. J., Reaume, A. G., Scott, R., et al. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01469-8 · Cited by 53 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- Bao, J., Sharp, A. H., Wagster, M. V., Becher, M., Schilling, G., Ross, C. A., Dawson, V. L. & Dawson, T. M. (1996) Proc. Natl. Acad. Sci. USA 93, 5037-5042.
- Gutekunst, C. A., Levey, A. I., Heilman, C. J., Whaley, W. L., Yi, H., Nash, N. R., Rees, H. D., Madden, J. J. & Hersch, S. M. (1995) Proc. Natl. Acad. Sci. USA 92, 8710-8714.
- Reiner, A., Albin, R. L., Anderson, K. D., D'Amato, C. J., Penney, J. B. & Young, A. B. (1988) Proc. Natl. Acad. Sci. USA 85, 5733-5737.
- Cha, J. H., Kosinski, C. M., Kerner, J. A., Alsdorf, S. A., Mangiarini, L., Davies, S. W., Penney, J. B., Bates, G. P. & Young, A. B. (1998) Proc. Natl. Acad. Sci. USA 95, 6480-6485.
- Marini, A. M. & Paul, S. M. (1992) Proc. Natl. Acad. Sci. USA 89, 6555-6559.
Cited by
Sorted by citations
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 · see citing works
Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling
Gorman, A. M. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00402.x · Cited by 362 · see citing works
Crapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N. (2020) · Brain · doi:10.1093/brain/awz363 · Cited by 157 · see citing works
Synaptic dysfunction in Huntington's disease: a new perspective
Smith, R., Brundin, P., & Li, J.-Y. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5084-5 · Cited by 166 · see citing works
Self-citationLuthi-Carter, R., Apostol, B. L., Dunah, A. W., DeJohn, M. M., Farrell, L. A., Bates, G. P., Young, A. B., Standaert, D. G., Thompson, L. M., & Cha, J.-H. J. (2003) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.08.024 · Cited by 104 · see citing works
- Authors
- Hansson, O., Petersén, Å., Leist, M., Nicotera, P., Castilho, R. F., & Brundin, P.
- Affiliations
- Lund University (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-07-20
- Volume
- 96
- Issue
- 15
- Pages
- 8727-8732
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC17584
- OpenAlex
- W2063375748
- Cited by
- 228
- References
- 50
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 12
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Thorsten och Elsa Segerfalks Stiftelse
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- Huntington's disease, quinolinic acid, NMDA receptor, neuroprotection, CAG repeat expansion, R6/1 transgenic mice, calbindin-D28k, superoxide dismutase, Bcl-2, HSP70, mitochondrial function, astrocytes
- MeSH terms
- Animals, Brain, Cell Count, Cell Survival, Corpus Striatum, Exons, Humans, Huntington Disease, Immunohistochemistry, Mice, Transgenic, Nerve Tissue Proteins, Neurotoxins, Biomarkers, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Quinolinic Acid, In Situ Nick-End Labeling, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
