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Post-translational modifications of neurodegenerative disease proteins

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  • Corresponding author: WANG Guang-hui, E-mail: wghui@ustc.edu.cn
  • Received Date: 28 June 2008
  • Rev Recd Date: 05 July 2008
  • Publish Date: 31 August 2008
    Abstract

  • Abstract

    Post-translational modifications of target proteins are important for these proteins to execute their cellular functions and enable cells to respond to stimuli. There are phosphorylation, acetylation, methylation, ubiquitination, SUMOylation and other modifications to modify target proteins. In the research of neurodegenerative diseases, post-translational modifications participate in the process and pathogenesis of the diseases attracting increasing attention. In this review, we discuss the relationship between neurodegenerative diseases and phosphorylation, ubiquitination or SUMOylation and introduce our laboratorys work.

    Abstract

    Post-translational modifications of target proteins are important for these proteins to execute their cellular functions and enable cells to respond to stimuli. There are phosphorylation, acetylation, methylation, ubiquitination, SUMOylation and other modifications to modify target proteins. In the research of neurodegenerative diseases, post-translational modifications participate in the process and pathogenesis of the diseases attracting increasing attention. In this review, we discuss the relationship between neurodegenerative diseases and phosphorylation, ubiquitination or SUMOylation and introduce our laboratorys work.
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    • References(43)
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    Jankovic J, Chen S, Le W D. The role of Nurr1 in the development of dopaminergic neurons and Parkinsons disease[J]. Prog Neurobiol, 2005, 77: 128-138.
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    Matunis M J, Coutavas E, Blobel G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex[J]. J Cell Biol, 1996, 135: 1 457-1 470.
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    Mahajan R, Delphin C, Guan T, et al. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2[J]. Cell, 1997, 88: 97-107.
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    Melchior F. SUMO—nonclassical ubiquitin[J]. Annu Rev Cell Dev Biol. 2000, 16: 591-626.
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    Guo D, Li M, Zhang Y, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes[J]. Nature Genetics, 2004, 36: 837-841.
    [29]
    Muller S, Ledl A, Schmidt D. SUMO: A regulator of gene expression and genome integrity[J]. Oncogene, 2004,23:1 998-2 008.
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    Yeh E T, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles[J]. Gene, 2000,248:1-14.
    [31]
    Martin S, Wilkinson K A, Nishimune A, et al. Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction[J]. Nature reviews, 2007,8:948-959.
    [32]
    Gill G. SUMO and ubiquitin in the nucleus: Different functions, similar mechanisms[J]. Genes Dev, 2004,18:2 046-2 059.
    [33]
    Johnson E S. Protein modification by SUMO[J]. Annu Rev Biochem, 2004,73:355-382.
    [34]
    Ueda H, Goto J, Hashida H, et al. Enhanced SUMOylation in polyglutamine diseases[J]. Biochem Biophys Res Commun, 2002,293:307-313.
    [35]
    汤建光，沈璐，唐北河，等. SUMO-1共价修饰ataxin-3[J]. 生物化学与生物物理进展, 2006,33:1 037-1 043.
    [36]
    Chan H Y, Warrick J M, Andriola I, et al. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila[J]. Hum Mol Genet,2002,11:2 895-2 904.
    [37]
    Shinbo Y, Niki T, Taira T, et al. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities[J]. Cell Death Differ, 2006,13:96-108.
    [38]
    Fan J, Ren H, Fei E, et al. Sumoylation is critical for DJ-1 to repress p53 transcriptional activity[J]. FEBS Lett, 2008,582:1 151-1 156.
    [39]
    Fan J, Ren H, Jia N, et al. DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity[J]. Journal of Biological Chemistry, 2008,283:4 022-4 030.
    [40]
    Fei E, Jia N, Yan M, et al. SUMO-1 modification increases human SOD1 stability and aggregation[J]. Biochem Biophys Res Co, 2006,347(2):406-412.
    [41]
    Martin S, Wilkinson K A, Nishimune A, et al. Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction[J]. Nature Reviews, 2007,8:948-959.
    [42]
    Ardley H C, Robinson P A. The role of ubiquitin-protein ligases in neurodegenerative disease[J]. Neurodegener Dis, 2004,1:71-87.
    [43]
    Alves-Rodrigues A, Gregori L, Figueiredo-Pereira M E. Ubiquitin, cellular inclusions and their role in neurodegeneration[J]. Trends Neurosci, 1998,21(12): 516-520.
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    [1]
    Lee V M, Goedert M, Trojanowski J Q. Neurodegenerative tauopathies[J]. Annu Rev Neurosci, 2001,24:1 121-1 159.
    [2]
    Lucas J J, Hernandez F, Gomez-Ramos P, et al. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice[J]. Embo J, 2001,20:27-39.
    [3]
    Jackson G R, Wiedau-Pazos M, Sang T K, et al. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila[J]. Neuron, 2002,34:509-519.
    [4]
    Fujiwara H, Hasegawa M, Dohmae N, et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions[J]. Nat Cell Biol, 2002,4:160-164.
    [5]
    Anderson J P, Walker D E, Goldstein J M, et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease[J]. J Biol Chem, 2006,281:29 739-29 752.
    [6]
    Okochi M, Walter J, Koyama A, et al. Constitutive phosphorylation of the Parkinsons disease associated alpha-synuclein[J]. J Biol Chem, 2000,275:390-397.
    [7]
    Liu C, Fei E, Jia N, et al. Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated alpha-synuclein implies Lewy body biogenesis[J]. J Biol Chem, 2007,282:14 558-14 566.
    [8]
    Chen H K, Fernandez-Funez P, Acevedo S F, et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1[J]. Cell, 2003,113:457-468.
    [9]
    Emamian E S, Kaytor M D, Duvick L A, et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice[J]. Neuron, 2003,38:375-387.
    [10]
    Humbert S, Bryson E A, Cordelieres F P, et al. The IGF-1/Akt pathway is neuroprotective in Huntingtons disease and involves Huntingtin phosphorylation by Akt[J]. Dev Cell, 2002,2:831-837.
    [11]
    Luo S, Vacher C, Davies J E, et al. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity[J]. J Cell Biol, 2005,169:647-656.
    [12]
    Warby S C, Chan E Y, Metzler M, et al. Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo[J]. Hum Mol Genet, 2005,14:1 569-1 577.
    [13]
    Okamura-Oho Y, Miyashita T, Nagao K, et al. Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH2-terminal kinase[J]. Hum Mol Genet, 2003,12:1 535-1 542.
    [14]
    Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q321[J]. Nat Genet, 1994,8:221-228.
    [15]
    Cummings C J, Zoghbi H Y. Trinucleotide repeats: mechanisms and pathophysiology[J]. Annual Review of Genomics and Human Genetics, 2000,1:281-328.
    [16]
    Matsumoto M, Yada M, Hatakeyama S, et al. Molecular clearance of ataxin-3 is regulated by a mammalian E4[J]. Embo J, 2004,23:659-669.
    [17]
    Paulson H L, Perez M K, Trottier Y, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3[J]. Neuron, 1997,19:333-344.
    [18]
    Fei E, Jia N, Zhang T, et al. Phosphorylation of ataxin-3 by glycogen synthase kinase 3b at serine 256 regulates the aggregation of ataxin-3[J]. Biochem Biophys Res Co, 2007, 357: 487-492.
    [19]
    Zhang T, Jia N, Fei E, et al. Nurr1 is phosphorylated by ERK2 in vitro and its phosphorylation upregulates tyrosine hydroxylase expression in SH-SY5Y cells[J]. Neuroscience Letters, 2007,423 :118-122.
    [20]
    Lotharius J, Brundin P. Pathogenesis of Parkinsons disease: dopamine, vesicles and alpha-synuclein[J]. Nat Rev Neurosci, 2002, 3:932-942.
    [21]
    Xu P Y, Liang R, Jankovic J, et al. Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinsons disease[J]. Neurology, 2002,58:881-884.
    [22]
    Zheng K, Heydari B, Simon D K. A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease[J]. Arch Neurol, 2003, 60: 722-725.
    [23]
    Le W D, Xu P, Jankovic J, et al. Mutations in NR4A2 associated with familial Parkinson disease[J]. Nat Genet, 2003, 33: 85-89.
    [24]
    Jankovic J, Chen S, Le W D. The role of Nurr1 in the development of dopaminergic neurons and Parkinsons disease[J]. Prog Neurobiol, 2005, 77: 128-138.
    [25]
    Matunis M J, Coutavas E, Blobel G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex[J]. J Cell Biol, 1996, 135: 1 457-1 470.
    [26]
    Mahajan R, Delphin C, Guan T, et al. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2[J]. Cell, 1997, 88: 97-107.
    [27]
    Melchior F. SUMO—nonclassical ubiquitin[J]. Annu Rev Cell Dev Biol. 2000, 16: 591-626.
    [28]
    Guo D, Li M, Zhang Y, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes[J]. Nature Genetics, 2004, 36: 837-841.
    [29]
    Muller S, Ledl A, Schmidt D. SUMO: A regulator of gene expression and genome integrity[J]. Oncogene, 2004,23:1 998-2 008.
    [30]
    Yeh E T, Gong L, Kamitani T. Ubiquitin-like proteins: new wines in new bottles[J]. Gene, 2000,248:1-14.
    [31]
    Martin S, Wilkinson K A, Nishimune A, et al. Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction[J]. Nature reviews, 2007,8:948-959.
    [32]
    Gill G. SUMO and ubiquitin in the nucleus: Different functions, similar mechanisms[J]. Genes Dev, 2004,18:2 046-2 059.
    [33]
    Johnson E S. Protein modification by SUMO[J]. Annu Rev Biochem, 2004,73:355-382.
    [34]
    Ueda H, Goto J, Hashida H, et al. Enhanced SUMOylation in polyglutamine diseases[J]. Biochem Biophys Res Commun, 2002,293:307-313.
    [35]
    汤建光，沈璐，唐北河，等. SUMO-1共价修饰ataxin-3[J]. 生物化学与生物物理进展, 2006,33:1 037-1 043.
    [36]
    Chan H Y, Warrick J M, Andriola I, et al. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila[J]. Hum Mol Genet,2002,11:2 895-2 904.
    [37]
    Shinbo Y, Niki T, Taira T, et al. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities[J]. Cell Death Differ, 2006,13:96-108.
    [38]
    Fan J, Ren H, Fei E, et al. Sumoylation is critical for DJ-1 to repress p53 transcriptional activity[J]. FEBS Lett, 2008,582:1 151-1 156.
    [39]
    Fan J, Ren H, Jia N, et al. DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity[J]. Journal of Biological Chemistry, 2008,283:4 022-4 030.
    [40]
    Fei E, Jia N, Yan M, et al. SUMO-1 modification increases human SOD1 stability and aggregation[J]. Biochem Biophys Res Co, 2006,347(2):406-412.
    [41]
    Martin S, Wilkinson K A, Nishimune A, et al. Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction[J]. Nature Reviews, 2007,8:948-959.
    [42]
    Ardley H C, Robinson P A. The role of ubiquitin-protein ligases in neurodegenerative disease[J]. Neurodegener Dis, 2004,1:71-87.
    [43]
    Alves-Rodrigues A, Gregori L, Figueiredo-Pereira M E. Ubiquitin, cellular inclusions and their role in neurodegeneration[J]. Trends Neurosci, 1998,21(12): 516-520.
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