Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95
Open accessAbstract
Increased glutamate-mediated excitotoxicity seems to play an important role in the pathogenesis of Huntington's disease (Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taaman, J. W., Cooper, J. M., and Schapira, A. H. (1999) Ann. Neurol. 45, 25-32). However, how polyglutamine expansion in huntingtin promotes glutamate-mediated excitotoxicity remains a mystery. In this study we provide evidence that (i) normal huntingtin is associated with N-methyl-d-aspartate (NMDA) and kainate receptors via postsynaptic density 95 (PSD-95), (ii) the SH3 domain of PSD-95 mediates its binding to huntingtin, and (iii) polyglutamine expansion interferes with the ability of huntingtin to interact with PSD-95. The expression of polyglutamine-expanded huntingtin causes sensitization of NMDA receptors and promotes neuronal apoptosis induced by glutamate. The addition of the NMDA receptor antagonist significantly attenuates neuronal toxicity induced by glutamate and polyglutamine-expanded huntingtin. The overexpression of normal huntingtin significantly inhibits neuronal toxicity mediated by NMDA or kainate receptors. Our results demonstrate that polyglutamine expansion impairs the ability of huntingtin to bind PSD-95 and inhibits glutamate-mediated excitotoxicity. These changes may be essential for the pathogenesis of Huntington's disease.
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mRNA and protein levels of PSD-95 and AMPA receptors are reduced in HD patients and animal models.
“Interestingly, the mRNA and protein levels of PSD-95 and AMPA receptors are reduced in HD patients and in animal models (Cha et al., 1998;Sun et al., 2001;Luthi-Carter et al., 2003).”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Sun et al., 2001
Mutant huntingtin aggregates could sequester proteins involved in synaptic transmission (such as PSD-95 and AMPA receptors) and lead to depletion of these proteins at their site of action.
“Mutant huntingtin aggregates could sequester proteins that are involved in synaptic transmission, such as the scaffolding protein PSD-95, and AMPA receptors among many others and lead to depletion of these proteins at their site of action (Cha et al., 1998;Sun et al., 2001;Luthi-Carter”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Sun et al., 2001
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“…in synaptic transmission, such as the scaffolding protein PSD-95, and AMPA receptors among many others and lead to depletion of these proteins at their site of action (Cha et al., 1998; Sun et al., 2001; Luthi-Carter et al., 2003; Smith et al., 2005a,b, 2007; Nithianantharajah and Hannan, 2012).”
BackgroundLuthi-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
Barron, J. C., Hurley, E. P., & Parsons, M. P. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.689332 · Cited by 85 · see citing works
- Authors
- Sun, Y., Savanenin, A., Reddy, P. H., & Liu, Y. F.
- Affiliations
- Northeastern University (US)
- Oregon Health & Science University (US)
- Corresponding author
- Liu, Ya Fang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 276
- Issue
- 27
- Pages
- 24713-24718
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2168620266
- Cited by
- 297
- References
- 4
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 11 · 2021: 8 · 2020: 6 · 2019: 13 · 2018: 11 · 2017: 7 · 2016: 14 · 2015: 13 · 2014: 16 · 2013: 8 · 2012: 21
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Huntington's disease, NMDA receptor, kainate receptors, PSD-95, SH3 domain, glutamate excitotoxicity, neuronal apoptosis, receptor sensitization, protein-protein interaction
- MeSH terms
- Huntingtin Protein, Disks Large Homolog 4 Protein, Animals, Cell Line, Humans, Huntington Disease, Membrane Proteins, Molecular Weight, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Peptides, Protein Binding, Transfection, Receptors, N-Methyl-D-Aspartate, Receptors, Kainic Acid, Kainic Acid Receptors, src Homology Domains, In Situ Nick-End Labeling, Intracellular Signaling Peptides and Proteins, Rats
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