The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin
Abstract
Huntington's disease (HD) is caused by abnormal polyglutamine (polyQ) expansion in the protein huntingtin. We have previously demonstrated the importance of the insulin-like growth factor I (IGF-1)/Akt pathway in HD. Indeed, upon IGF-1 activation, Akt phosphorylates polyQ-huntingtin at serine 421 and abrogates its toxicity. In addition, we have demonstrated that Akt is altered in the brain of HD patients. Here, we investigate the role of the serum- and glucocorticoid-induced kinase (SGK) in HD. We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ-huntingtin-induced toxicity. We find that SGK levels are increased in the brain of HD patients. Using a cellular model of HD, we demonstrate that the SGK dysregulation induced by polyQ-huntingtin occurs via the p38/MAPK pathway. Collectively, our results strongly suggest the involvement of SGK in HD and further imply that IGF-1 downstream signalling is a key transduction pathway that regulates the toxicity of huntingtin.
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Total SGK protein levels, encompassing SGK1 and SGK3, show an upregulation trend in brains of Huntington's disease patients, with concentration increasing as disease severity progresses.
“Total SGK protein levels, encompassing both SGK1 and SGK3, show an upregulation trend in the brains of HD patients, with the concentration increasing as the severity of the disease progresses”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Rangone et al., 2004
SGK phosphorylates huntingtin protein at serine 421, and this phosphorylation can protect striatal neurons from toxicity of mutant huntingtin protein.
“Moreover, SGK phosphorylates huntingtin protein at serine 421, and this phosphorylation can protect striatal neurons from the toxicity of mutant huntingtin protein”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Rangone et al., 2004
SGK1 is a potent antioxidant and has been implicated in pathogenesis of Huntington's disease.
“SGK1 is a potent antioxidant and has been implicated in the pathogenesis of HD”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Rangone et al., 2004
Cites
Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Panov, A. V., Gutekunst, C.-A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., & Greenamyre, J. T. (2002) · Nature Neuroscience · doi:10.1038/nn884 · Cited by 1,030 · see citing works
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(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms
Lang, F., Böhmer, C., Palmada, M., Seebohm, G., Strutz-Seebohm, N., & Vallon, V. (2006) · Physiological Reviews · doi:10.1152/physrev.00050.2005 · Cited by 689 · see citing works
Pich, S., Bach, D., Briones, P., Liesa, M., Camps, M., Testar, X., Palacín, M., & Zorzano, A. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi149 · Cited by 455 · see citing works
Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration
Spielman, L. J., Little, J. P., & Klegeris, A. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.06.004 · Cited by 182 · see citing works
Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Rangone, H., Poizat, G., Troncoso, J., Ross, C. A., MacDonald, M. E., Saudou, F., & Humbert, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Johns Hopkins University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Humbert, Sandrine
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2004-01
- Volume
- 19
- Issue
- 2
- Pages
- 273-279
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W2151732475
- Cited by
- 144
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 10 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 6 · 2015: 9 · 2014: 12 · 2013: 6 · 2012: 8
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS16375)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, huntingtin, polyglutamine expansion, SGK, Akt signaling, IGF-1 signaling, p38 MAPK pathway, striatal neurons, neuroprotection, protein kinase signaling
- MeSH terms
- Huntingtin Protein, Serum-Glucocorticoid Regulated Kinases, Animals, Brain, Cell Line, Cells, Cultured, Female, Humans, Huntington Disease, Insulin-Like Growth Factor I, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Phosphorylation, Pregnancy, Serine, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Rats
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