泛素蛋白酶體系統在癲癇機制的研究_Journal of Epilepsy

Authors：

劉夢佳 ,  鄒麗萍

1. ;
2. ;

Corresponding?author：

鄒麗萍, Email: zouliping21@hotmail.com

Keywords：

癲癇; 泛素蛋白酶體系統; 精準醫療; Lafora病

DOI：

10.7507/2096-0247.20170018

Video：

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癲癇作為一種常見的兒童神經系統疾病對患者及其家庭造成了沉重的負擔，目前精準、個體化的治療還有相當的困難。泛素蛋白酶體系統的異常在癲癇的發病中具有一定的作用，對它們之間關系的總結有利于更準確的診斷和治療。現從以下幾個方面進行綜述：①泛素蛋白酶體系統在伴有癲癇的特殊綜合征中的作用；②基于動物實驗的泛素蛋白酶體系統與癲癇相關性的研究。文章展示了臨床以及基礎研究中泛素蛋白酶體系統和癲癇之間的關聯性。在臨床表現上，泛素蛋白酶體系統的異常可以造成各種伴有癲癇的綜合征，或作為癲癇發生的生物標記物；在發病機制上，其異常可以通過促進神經元的興奮性或者凋亡進程造成癲癇的發生。表明泛素蛋白連接酶體系統異常是癲癇發生的原因之一。

Citation： 劉夢佳, 鄒麗萍. 泛素蛋白酶體系統在癲癇機制的研究. Journal of Epilepsy, 2017, 3(2): 126-131. doi: 10.7507/2096-0247.20170018 Copy

1.	Paemka L, Mahajan VB, Ehaideb SN, et al. Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase. PLoS Genet, 2015, 11(3): e1005022.
2.	Rao SN, Skeie JM, Tan MC, et al. Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum Mol Genet, 2010, 19(23): 4726-4734.
3.	Ciechanover A, Schwartz AL. The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci USA, 1998, 95(6): 2727-2730.
4.	Mittal S, Wu S, Cox AJ, et al. Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. Hum Mol Genet, 2007, 16(7): 753-762.
5.	Minassian BA, Sowers LP, Gecz J. Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol, 2001, 25(1): 21-29.
6.	Delgado-Escueta AV. Advances in lafora progressive myoclonus epilepsy. Curr Neurol Neurosci Rep, 2007, 7(5): 428-433.
7.	Gentry MS, CA Worby, JE Dixon. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci USA, 2005, 102(24): 8501-8506.
8.	Garyali P, Olly L, Ferguson PJ, et al. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet, 2009, 18(4): 688-700.
9.	Vernia S, Darbro B, Schneider A, et al. Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS One, 2009, 4(6): e5907.
10.	Morimoto RI. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev, 2008, 22(11): 1427-1438.
11.	Sengupta S, Scheffer IE, Carvill GL, et al. Malin and laforin are essential components of a protein complex that protects cells from thermal stress. J Cell Sci, 2011, 124(Pt 13): 2277-2286.
12.	Rao SN, Mefford HC, El-Shanti H, et al. Co-chaperone CHIP stabilizes aggregate-prone malin, a ubiquitin ligase mutated in Lafora disease. J Biol Chem, 2010, 285(2): 1404-1413.
13.	Moreno D, Wood SA, Manak JR, et al. The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. Mol Biol Cell, 2010, 21(15): 2578-2588.
14.	Lohi H, Bassuk AG, Ianzano L, et al. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet, 2005, 14(18): 2727-2736.
15.	Rubio-Villena, CMA Garcia-Gimeno, P Sanz. Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int J Biochem Cell Biol, 2013, 45(7): 1479-1488.
16.	Criado O, Zhao XC, Chan EM, et al. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet, 2012, 21(7): 1521-1533.
17.	Singh S, Turnbull J, Scherer SW, et al. Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a. RNA Biol, 2012, 9(12): 1440-1449.
18.	Singh PK, Ganeshb S. Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease. Mol Biol Cell, 2013, 24(24): 3776-3786.
19.	Santini E, Klann E. Genetically dissecting cortical neurons involved in epilepsy in angelman syndrome. Neuron, 2016, 90(1): 1-3.
20.	Tan WH, Ackerley CA, Minassian BA, et al. Angelman syndrome: mutations influence features in early childhood. Am J Med Genet A, 2011, 155 (1): 81-90.
21.	Jiang YH, Armstrong D, Albrecht U, et al. Mutation of the angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron, 1998, 21(4): 799-811.
22.	Kuhnle S, Atkins CM, Noebels JL, et al. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci USA, 2013, 110(22): 8888-8893.
23.	Nicita F, Eichele G, Sweatt JD, et al. Myoclonic status and central fever in Angelman syndrome due to paternal uniparental disomy. J Neurogenet, 2015, 29(4): 178-182.
24.	Ropers HH. X-linked mental retardation. Advances in Genetics, 2005, 41(6): 46-57.
25.	Tarpey PS, Garone G, Papetti L, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet, 2007, 80(2): 345-352.
26.	Miranda E, Consoli F, Magliozzi M, et al. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Human Molecular Genetics, 2008, 17(11): 1527-1539.
27.	Roussel BD, De Luca A, Spalice A, et al. Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB. Hum Mol Genet, 2013, 22(22): 4616-4626.
28.	Mcdonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nature Genetics, 2013, 45(5): 556-562.
29.	McDonell LM, Schwartzentruber J, Carter MT, et al. Novel STAMBP mutation and additional findings in an Arabic family. Nat Genet, 2012, 44(7): 317-322.
30.	Furukawa M, T Ohta, Y Xiong. Activation of UBC5 ubiquitin-conjugating enzyme by the RING finger of ROC1 and assembly of active ubiquitin ligases by all cullins. Journal of Biological Chemistry, 2002, 277(18): 15758-15765.
31.	Benari Y, R Cossart. Kainate, a double agent that generates seizures: two decades of progress. Trends in Neurosciences, 2000, 23(23): 580-587.
32.	Wang D, Lee LJ, Clericuzio CL, et al. Gene expression profile analysis in epilepsy by using the partial least squares method. Scientific World Journal, 2014, 8(5): 731091.
33.	Marshall J, LA Blair, JD Singer. BTB-Kelch proteins and ubiquitination of kainate receptors. Adv Exp Med Biol, 2011, 717(2): 115-125.
34.	Hortopan GA, MT Dinday, SC Baraban. Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish. J Neurosci, 2010, 30(41): 13718-13728.
35.	Dibbens LM, Graham JM Jr, Morris-Rosendahl DJ, et al. NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes Brain Behav, 2007, 6(8): 750-755.
36.	Wu L, Polster T, Acsadi G, et al. The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy. Physiol Behav, 2015, 143(2): 104-112.
37.	Liu J, Williams S, Halbert A, et al. CRL4A (CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis. Nat Commun, 2014, 5(1): 3924.
38.	Lavin MF, N Gueven. The complexity of p53 stabilization and activation. Cell Death Differ, 2006, 13(6): 941-950.
39.	Engel T, Isidor B, David A, et al. CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. Brain, 2013, 136(Pt 2): 577-592.
40.	Engel T, Paciorkowski AR, Willing M, et al. Elevated p53 and lower MDM2 expression in hippocampus from patients with intractable temporal lobe epilepsy. Epilepsy Res, 2007, 77(2-3): 151-156.
41.	Zhang J, Woulfe J, Das S, et al. Activation of GluR6-containing kainate receptors induces ubiquitin-dependent Bcl-2 degradation via denitrosylation in the rat hippocampus after kainate treatment. J Biol Chem, 2011, 286(9): 7669-7680.
42.	Mondello S, Beaulieu CL, Marcadier J, et al. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol, 2012, 12(2): 85.
43.	Li Y, Geraghty MT, Frey BJ, et al. Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure. Epilepsy Res, 2013, 103(2-3): 205-210.
44.	Hilary CMartin, Bulman DE, Dobyns WB, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.

1. Paemka L, Mahajan VB, Ehaideb SN, et al. Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase. PLoS Genet, 2015, 11(3): e1005022.
2. Rao SN, Skeie JM, Tan MC, et al. Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum Mol Genet, 2010, 19(23): 4726-4734.
3. Ciechanover A, Schwartz AL. The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci USA, 1998, 95(6): 2727-2730.
4. Mittal S, Wu S, Cox AJ, et al. Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment. Hum Mol Genet, 2007, 16(7): 753-762.
5. Minassian BA, Sowers LP, Gecz J. Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol, 2001, 25(1): 21-29.
6. Delgado-Escueta AV. Advances in lafora progressive myoclonus epilepsy. Curr Neurol Neurosci Rep, 2007, 7(5): 428-433.
7. Gentry MS, CA Worby, JE Dixon. Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci USA, 2005, 102(24): 8501-8506.
8. Garyali P, Olly L, Ferguson PJ, et al. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet, 2009, 18(4): 688-700.
9. Vernia S, Darbro B, Schneider A, et al. Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS One, 2009, 4(6): e5907.
10. Morimoto RI. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev, 2008, 22(11): 1427-1438.
11. Sengupta S, Scheffer IE, Carvill GL, et al. Malin and laforin are essential components of a protein complex that protects cells from thermal stress. J Cell Sci, 2011, 124(Pt 13): 2277-2286.
12. Rao SN, Mefford HC, El-Shanti H, et al. Co-chaperone CHIP stabilizes aggregate-prone malin, a ubiquitin ligase mutated in Lafora disease. J Biol Chem, 2010, 285(2): 1404-1413.
13. Moreno D, Wood SA, Manak JR, et al. The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. Mol Biol Cell, 2010, 21(15): 2578-2588.
14. Lohi H, Bassuk AG, Ianzano L, et al. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet, 2005, 14(18): 2727-2736.
15. Rubio-Villena, CMA Garcia-Gimeno, P Sanz. Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int J Biochem Cell Biol, 2013, 45(7): 1479-1488.
16. Criado O, Zhao XC, Chan EM, et al. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet, 2012, 21(7): 1521-1533.
17. Singh S, Turnbull J, Scherer SW, et al. Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a. RNA Biol, 2012, 9(12): 1440-1449.
18. Singh PK, Ganeshb S. Activation of serum/glucocorticoid-induced kinase 1 (SGK1) underlies increased glycogen levels, mTOR activation, and autophagy defects in Lafora disease. Mol Biol Cell, 2013, 24(24): 3776-3786.
19. Santini E, Klann E. Genetically dissecting cortical neurons involved in epilepsy in angelman syndrome. Neuron, 2016, 90(1): 1-3.
20. Tan WH, Ackerley CA, Minassian BA, et al. Angelman syndrome: mutations influence features in early childhood. Am J Med Genet A, 2011, 155 (1): 81-90.
21. Jiang YH, Armstrong D, Albrecht U, et al. Mutation of the angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron, 1998, 21(4): 799-811.
22. Kuhnle S, Atkins CM, Noebels JL, et al. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci USA, 2013, 110(22): 8888-8893.
23. Nicita F, Eichele G, Sweatt JD, et al. Myoclonic status and central fever in Angelman syndrome due to paternal uniparental disomy. J Neurogenet, 2015, 29(4): 178-182.
24. Ropers HH. X-linked mental retardation. Advances in Genetics, 2005, 41(6): 46-57.
25. Tarpey PS, Garone G, Papetti L, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet, 2007, 80(2): 345-352.
26. Miranda E, Consoli F, Magliozzi M, et al. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Human Molecular Genetics, 2008, 17(11): 1527-1539.
27. Roussel BD, De Luca A, Spalice A, et al. Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB. Hum Mol Genet, 2013, 22(22): 4616-4626.
28. Mcdonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nature Genetics, 2013, 45(5): 556-562.
29. McDonell LM, Schwartzentruber J, Carter MT, et al. Novel STAMBP mutation and additional findings in an Arabic family. Nat Genet, 2012, 44(7): 317-322.
30. Furukawa M, T Ohta, Y Xiong. Activation of UBC5 ubiquitin-conjugating enzyme by the RING finger of ROC1 and assembly of active ubiquitin ligases by all cullins. Journal of Biological Chemistry, 2002, 277(18): 15758-15765.
31. Benari Y, R Cossart. Kainate, a double agent that generates seizures: two decades of progress. Trends in Neurosciences, 2000, 23(23): 580-587.
32. Wang D, Lee LJ, Clericuzio CL, et al. Gene expression profile analysis in epilepsy by using the partial least squares method. Scientific World Journal, 2014, 8(5): 731091.
33. Marshall J, LA Blair, JD Singer. BTB-Kelch proteins and ubiquitination of kainate receptors. Adv Exp Med Biol, 2011, 717(2): 115-125.
34. Hortopan GA, MT Dinday, SC Baraban. Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish. J Neurosci, 2010, 30(41): 13718-13728.
35. Dibbens LM, Graham JM Jr, Morris-Rosendahl DJ, et al. NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes Brain Behav, 2007, 6(8): 750-755.
36. Wu L, Polster T, Acsadi G, et al. The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy. Physiol Behav, 2015, 143(2): 104-112.
37. Liu J, Williams S, Halbert A, et al. CRL4A (CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis. Nat Commun, 2014, 5(1): 3924.
38. Lavin MF, N Gueven. The complexity of p53 stabilization and activation. Cell Death Differ, 2006, 13(6): 941-950.
39. Engel T, Isidor B, David A, et al. CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. Brain, 2013, 136(Pt 2): 577-592.
40. Engel T, Paciorkowski AR, Willing M, et al. Elevated p53 and lower MDM2 expression in hippocampus from patients with intractable temporal lobe epilepsy. Epilepsy Res, 2007, 77(2-3): 151-156.
41. Zhang J, Woulfe J, Das S, et al. Activation of GluR6-containing kainate receptors induces ubiquitin-dependent Bcl-2 degradation via denitrosylation in the rat hippocampus after kainate treatment. J Biol Chem, 2011, 286(9): 7669-7680.
42. Mondello S, Beaulieu CL, Marcadier J, et al. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol, 2012, 12(2): 85.
43. Li Y, Geraghty MT, Frey BJ, et al. Cerebrospinal fluid ubiquitin C-terminal hydrolase as a novel marker of neuronal damage after epileptic seizure. Epilepsy Res, 2013, 103(2-3): 205-210.
44. Hilary CMartin, Bulman DE, Dobyns WB, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.

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泛素蛋白酶體系統在癲癇機制的研究

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