Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis - PubMed (original) (raw)
. 2007 Apr;48(4):1683-90.
doi: 10.1167/iovs.06-0943.
Affiliations
- PMID: 17389500
- DOI: 10.1167/iovs.06-0943
Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis
Gary Hin-Fai Yam et al. Invest Ophthalmol Vis Sci. 2007 Apr.
Abstract
Purpose: To evaluate the effect of chemical chaperones on the trafficking of secretion-incompetent primary open-angle glaucoma-associated mutant myocilin and the possibility to rescue cells coexpressing mutant and wild-type myocilin from endoplasmic reticulum (ER) stress and apoptosis.
Methods: CHO-K1, HEK293 and human trabecular meshwork cells were transfected to express wild-type or mutant (C245Y, G364V, P370L, Y437H) myocilin-green fluorescent protein fusion protein and were treated or not with various chemical chaperones (glycerol, dimethylsulfoxide, or sodium 4-phenylbutyrate) for different time periods. The secretion, Triton X-100 solubility, and intracellular distribution of wild-type and mutant myocilin were analyzed by immunoprecipitation, Western blotting, and confocal double immunofluorescence. The effect of sodium 4-phenylbutyrate on ER stress proteins and apoptosis was examined in cells coexpressing mutant and wild-type myocilin.
Results: Treatment with sodium 4-phenylbutyrate, but not with glycerol or dimethylsulfoxide, reduced the amount of detergent-insoluble myocilin aggregates, diminished myocilin interaction with calreticulin, and restored the secretion of mutant myocilin. Heteromeric complexes formed by mutant and wild-type myocilin induced the ER stress-associated phosphorylated form of ER-localized eukaryotic initiation factor (eIF)-2alpha kinase and the active form of caspase 3, which resulted in an increased rate of apoptosis. Sodium 4-phenylbutyrate treatment of cells coexpressing mutant and wild-type myocilin relieved ER stress and significantly reduced the rate of apoptosis.
Conclusions: These findings indicate that sodium 4-phenylbutyrate protects cells from the deleterious effects of ER-retained aggregated mutant myocilin. These data point to the possibility of a chemical chaperone treatment for myocilin-caused primary open-angle glaucoma.
Similar articles
- Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma.
Stothert AR, Fontaine SN, Sabbagh JJ, Dickey CA. Stothert AR, et al. Exp Eye Res. 2016 Mar;144:38-45. doi: 10.1016/j.exer.2015.08.017. Epub 2015 Aug 22. Exp Eye Res. 2016. PMID: 26302411 Free PMC article. Review. - Aggregated myocilin induces russell bodies and causes apoptosis: implications for the pathogenesis of myocilin-caused primary open-angle glaucoma.
Yam GH, Gaplovska-Kysela K, Zuber C, Roth J. Yam GH, et al. Am J Pathol. 2007 Jan;170(1):100-9. doi: 10.2353/ajpath.2007.060806. Am J Pathol. 2007. PMID: 17200186 Free PMC article. - Expression of wild-type and truncated myocilins in trabecular meshwork cells: their subcellular localizations and cytotoxicities.
Sohn S, Hur W, Joe MK, Kim JH, Lee ZW, Ha KS, Kee C. Sohn S, et al. Invest Ophthalmol Vis Sci. 2002 Dec;43(12):3680-5. Invest Ophthalmol Vis Sci. 2002. PMID: 12454036 - A review of genetic and structural understanding of the role of myocilin in primary open angle glaucoma.
Kanagavalli J, Pandaranayaka E, Krishnadas SR, Krishnaswamy S, Sundaresan P. Kanagavalli J, et al. Indian J Ophthalmol. 2004 Dec;52(4):271-80. Indian J Ophthalmol. 2004. PMID: 15693317 Review.
Cited by
- 4-Phenyl butyric acid prevents glucocorticoid-induced osteoblast apoptosis by attenuating endoplasmic reticulum stress.
Yang J, Wu Q, Lv J, Nie H. Yang J, et al. J Bone Miner Metab. 2017 Jul;35(4):366-374. doi: 10.1007/s00774-016-0778-3. Epub 2016 Sep 27. J Bone Miner Metab. 2017. PMID: 27678165 - Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma.
Stothert AR, Fontaine SN, Sabbagh JJ, Dickey CA. Stothert AR, et al. Exp Eye Res. 2016 Mar;144:38-45. doi: 10.1016/j.exer.2015.08.017. Epub 2015 Aug 22. Exp Eye Res. 2016. PMID: 26302411 Free PMC article. Review. - Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.
Ansari U, Alam M, Nadora D, Muttalib Z, Chen V, Taguinod I, FitzPatrick M, Wen J, Ansari Z, Lui F. Ansari U, et al. AIMS Neurosci. 2024 Apr 30;11(2):166-177. doi: 10.3934/Neuroscience.2024010. eCollection 2024. AIMS Neurosci. 2024. PMID: 38988889 Free PMC article. Review. - A Novel Luciferase Assay For Sensitively Monitoring Myocilin Variants in Cell Culture.
Zadoo S, Nguyen A, Zode G, Hulleman JD. Zadoo S, et al. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):1939-50. doi: 10.1167/iovs.15-18789. Invest Ophthalmol Vis Sci. 2016. PMID: 27092720 Free PMC article. - Gestational Hypoxia Inhibits Pregnancy-Induced Upregulation of Ca2+ Sparks and Spontaneous Transient Outward Currents in Uterine Arteries Via Heightened Endoplasmic Reticulum/Oxidative Stress.
Hu XQ, Song R, Romero M, Dasgupta C, Min J, Hatcher D, Xiao D, Blood A, Wilson SM, Zhang L. Hu XQ, et al. Hypertension. 2020 Sep;76(3):930-942. doi: 10.1161/HYPERTENSIONAHA.120.15235. Epub 2020 Jul 20. Hypertension. 2020. PMID: 32683903 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials