Review Special Issues

SUMO modulation of protein aggregation and degradation

  • Received: 14 July 2015 Accepted: 30 August 2015 Published: 08 September 2015
  • Small ubiquitin-like modifier (SUMO) conjugation and binding to target proteins regulate a wide variety of cellular pathways. The functional aspects of SUMOylation include changes in protein-protein interactions, intracellular trafficking as well as protein aggregation and degradation. SUMO has also been linked to specialized cellular pathways such as neuronal development and synaptic transmission. In addition, SUMOylation is associated with neurological diseases associated with abnormal protein accumulations. SUMOylation of the amyloid and tau proteins involved in Alzheimer's disease and other tauopathies may contribute to changes in protein solubility and proteolytic processing. Similar events have been reported for α-synuclein aggregates found in Parkinson's disease, polyglutamine disorders such as Huntington's disease as well as protein aggregates found in amyotrophic lateral sclerosis (ALS). This review provides a detailed overview of the impact SUMOylation has on the etiology and pathology of these related neurological diseases.

    Citation: Marco Feligioni, Serena Marcelli, Erin Knock, Urooba Nadeem, Ottavio Arancio, Paul E. Fraser. SUMO modulation of protein aggregation and degradation[J]. AIMS Molecular Science, 2015, 2(4): 382-410. doi: 10.3934/molsci.2015.4.382

    Related Papers:

  • Small ubiquitin-like modifier (SUMO) conjugation and binding to target proteins regulate a wide variety of cellular pathways. The functional aspects of SUMOylation include changes in protein-protein interactions, intracellular trafficking as well as protein aggregation and degradation. SUMO has also been linked to specialized cellular pathways such as neuronal development and synaptic transmission. In addition, SUMOylation is associated with neurological diseases associated with abnormal protein accumulations. SUMOylation of the amyloid and tau proteins involved in Alzheimer's disease and other tauopathies may contribute to changes in protein solubility and proteolytic processing. Similar events have been reported for α-synuclein aggregates found in Parkinson's disease, polyglutamine disorders such as Huntington's disease as well as protein aggregates found in amyotrophic lateral sclerosis (ALS). This review provides a detailed overview of the impact SUMOylation has on the etiology and pathology of these related neurological diseases.

    [1] Feligioni M, Nisticò R (2013) SUMO: a (oxidative) stressed protein. Neuromolecular Med 15: 707-719. doi: 10.1007/s12017-013-8266-6
    [2] Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8: 947-956. doi: 10.1038/nrm2293
    [3] Krumova P, Weishaupt JH (2013) Sumoylation in neurodegenerative diseases. Cell Mol Life Sci 70: 2123-2138. doi: 10.1007/s00018-012-1158-3
    [4] Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer's disease. Lancet 368: 387-403. doi: 10.1016/S0140-6736(06)69113-7
    [5] Goedert M, Spillantini MG (2006) A century of Alzheimer's disease. Science 314: 777-871. doi: 10.1126/science.1132814
    [6] Tiraboschi P, Hansen LA, Thal LJ, et al. (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62: 1984-1989. doi: 10.1212/01.WNL.0000129697.01779.0A
    [7] LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 8: 499-509. doi: 10.1038/nrn2168
    [8] McGeer EG, McGeer PL (2010) Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. J Alzheimers Dis 19: 355-361.
    [9] Garwood CJ, Pooler AM, Atherton J, et al. (2011) Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2: e167. doi: 10.1038/cddis.2011.50
    [10] Lee L, Dale E, Staniszewski A, et al. (2014) Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease. Sci Rep 4: 7190. doi: 10.1038/srep07190
    [11] Ahn K, Song JH, Kim DK, et al. (2009) Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: a genetic association study. Neurosci Lett 465: 272-275. doi: 10.1016/j.neulet.2009.09.017
    [12] Grupe A, Abraham R, Li Y, et al. (2007) Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16: 865-873. doi: 10.1093/hmg/ddm031
    [13] Corneveaux JJ, Myers AJ, Allen AN, et al. (2010) Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 19: 3295-3301. doi: 10.1093/hmg/ddq221
    [14] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356. doi: 10.1126/science.1072994
    [15] Nisticò R, Ferraina C, Marconi V, et al. (2014) Age-related changes of protein SUMOylation balance in the AβPP Tg2576 mouse model of Alzheimer's disease. Front Pharmacol 5: 63.
    [16] McMillan LE, Brown JT, Henley JM, et al. (2011) Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model. Neurosci Lett 502: 201-208. doi: 10.1016/j.neulet.2011.07.045
    [17] Yun S-M, Cho S-J, Song JC, et al. (2012) SUMO1 modulates Aβ generation via BACE1 accumulation. Neurobiol Aging 34: 650-662.
    [18] Yang Q-G, Wang F, Zhang Q, et al. (2012) Correlation of increased hippocampal Sumo3 with spatial learning ability in old C57BL/6 mice. Neurosci Lett518: 75-79.
    [19] Matsuzaki S, Lee L, Knock E, et al. (2015) SUMO1 Affects Synaptic Function, Spine Density and Memory. Sci Rep 5: 10730. doi: 10.1038/srep10730
    [20] Gocke CB, Yu H, Kang J (2005) Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates. J Biol Chem 280: 5004-5012. doi: 10.1074/jbc.M411718200
    [21] Zhang Y-Q, Sarge KD (2008) Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels. Biochem Biophys Res Commun 374: 673-678. doi: 10.1016/j.bbrc.2008.07.109
    [22] Tatham MH, Jaffray E, Vaughan OA, et al. (2001) Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem 276: 35368-35374. doi: 10.1074/jbc.M104214200
    [23] Li Y, Wang H, Wang S, et al. (2003) Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A 100: 259-264. doi: 10.1073/pnas.0235361100
    [24] Dorval V, Mazzella MJ, Mathews PM, et al. (2007) Modulation of Abeta generation by small ubiquitin-like modifiers does not require conjugation to target proteins. Biochem J 404: 309-316. doi: 10.1042/BJ20061451
    [25] Mullan M, Crawford F, Axelman K, et al. (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1: 345-347. doi: 10.1038/ng0892-345
    [26] Sarge KD, Park-Sarge O-K (2011) SUMO and its role in human diseases. Int Rev Cell Mol Biol 288: 167-183. doi: 10.1016/B978-0-12-386041-5.00004-2
    [27] Feligioni M, Brambilla E, Camassa A, et al. (2011) Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury. PLoS One 6: e28185. doi: 10.1371/journal.pone.0028185
    [28] Schweers O, Schonbrunn-Hanebeck E, Marx A, et al. (1994) Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem 269: 24290-24297.
    [29] Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11: 739-756. doi: 10.1110/ps.4210102
    [30] Wang J-Z, Liu F (2008) Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85: 148-175. doi: 10.1016/j.pneurobio.2008.03.002
    [31] Goedert M (2004) Tau protein and neurodegeneration. Semin Cell Dev Biol 15: 45-49. doi: 10.1016/j.semcdb.2003.12.015
    [32] Ingram EM, Spillantini MG (2002) Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol Med 8: 555-562. doi: 10.1016/S1471-4914(02)02440-1
    [33] Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24: 1121-1159. doi: 10.1146/annurev.neuro.24.1.1121
    [34] Shahani N, Brandt R (2002) Functions and malfunctions of the tau proteins. Cell Mol Life Sci 59: 1668-1680. doi: 10.1007/PL00012495
    [35] Brandt R, Hundelt M, Shahani N (2005) Tau alteration and neuronal degeneration in tauopathies: mechanisms and models. Biochim Biophys Acta 1739: 331-354. doi: 10.1016/j.bbadis.2004.06.018
    [36] Braak F, Braak H, Mandelkow E-M (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87: 554-567. doi: 10.1007/BF00293315
    [37] Grundke-Iqbal I, Iqbal K, Tung YC, et al. (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83: 4913-4917. doi: 10.1073/pnas.83.13.4913
    [38] Iqbal K, Alonso A del C, Grundke-Iqbal I (2008) Cytosolic abnormally hyperphosphorylated tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. J Alzheimers Dis 14: 365-370.
    [39] Iqbal K, Grundke-Iqbal I (1991) Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer's disease. Mol Neurobiol 5: 399-410. doi: 10.1007/BF02935561
    [40] Iqbal K, Grundke-Iqbal I (2008) Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J Cell Mol Med 12: 38-55.
    [41] Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2: 783-787. doi: 10.1038/nm0796-783
    [42] Kopke E, Tung Y, Shaikh S, et al. (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non- paired helical filament pool in Alzheimer disease. J Biol Chem 268: 24374-24384.
    [43] Dorval V, Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem 281: 9919-9924. doi: 10.1074/jbc.M510127200
    [44] Dorval V, Fraser PE (2007) SUMO on the road to neurodegeneration. Biochim Biophys Acta 1773: 694-706. doi: 10.1016/j.bbamcr.2007.03.017
    [45] Takahashi K, Ishida M, Komano H, et al. (2008) SUMO-1 immunoreactivity co-localizes with phospho-Tau in APP transgenic mice but not in mutant Tau transgenic mice. Neurosci Lett 441: 90-93. doi: 10.1016/j.neulet.2008.06.012
    [46] Pountney D, Huang Y, Burns R, et al. (2003) SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease. Exp Neurol 184: 436-446. doi: 10.1016/j.expneurol.2003.07.004
    [47] Luo H-B, Xia Y-Y, Shu X-J, et al. (2014) SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A 111: 16586-16591. doi: 10.1073/pnas.1417548111
    [48] Fukuda I, Ito A, Hirai G, et al. (2009) Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol 16: 133-140. doi: 10.1016/j.chembiol.2009.01.009
    [49] Gong CX, Lidsky T, Wegiel J, et al. (2000) Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem 275: 5535-5544.
    [50] Gamblin TC (2005) Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta - Mol Basis Dis 1739: 140-149. doi: 10.1016/j.bbadis.2004.08.013
    [51] Eun Jeoung L, Sung Hee H, Jaesun C, et al. (2008) Regulation of glycogen synthase kinase 3beta functions by modification of the small ubiquitin-like modifier. Open Biochem J 2: 67-76. doi: 10.2174/1874091X00802010067
    [52] Mattson MP (2001) Neuronal death and GSK-3β: a tau fetish? Trends Neurosci 24: 255-256.
    [53] Takashima A (2006) GSK-3 is essential in the pathogenesis of Alzheimer's disease. J Alzheimers Dis 9: 309-317.
    [54] Wang GP, Grundke-Iqbal I, Kascsak RJ, et al. (1984) Alzheimer neurofibrillary tangles: monoclonal antibodies to inherent antigen(s). Acta Neuropathol 62: 268-275. doi: 10.1007/BF00687608
    [55] Hay RT (2005) SUMO: a history of modification. Mol Cell 18: 1-12. doi: 10.1016/j.molcel.2005.03.012
    [56] Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82: 373-428. doi: 10.1152/physrev.00027.2001
    [57] Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235: 1641-1644. doi: 10.1126/science.3029875
    [58] Perry G, Friedman R, Shaw G, et al. (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A 84: 3033-3036. doi: 10.1073/pnas.84.9.3033
    [59] Manetto V, Perry G, Tabaton M, et al. Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases. Proc Natl Acad Sci U S A 85: 4501-4505.
    [60] Cripps D, Thomas SN, Jeng Y, et al. (2006) Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem 281: 10825-10838. doi: 10.1074/jbc.M512786200
    [61] Vincent IJ, Davies P (1990) ATP-induced loss of Alz-50 immunoreactivity with the A68 proteins from Alzheimer brain is mediated by ubiquitin. Proc Natl Acad Sci U S A 87: 4840-4844. doi: 10.1073/pnas.87.12.4840
    [62] García-Sierra F, Jarero-Basulto JJ, Kristofikova Z, et al. (2012) Ubiquitin is associated with early truncation of tau protein at aspartic acid(421) during the maturation of neurofibrillary tangles in Alzheimer's disease. Brain Pathol 22: 240-250. doi: 10.1111/j.1750-3639.2011.00525.x
    [63] Corsetti V, Florenzano F, Atlante A, et al. (2015) NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. Hum Mol Genet 24: 3058-3081. doi: 10.1093/hmg/ddv059
    [64] Bednarski E, Lynch G (1996) Cytosolic proteolysis of tau by cathepsin D in hippocampus following suppression of cathepsins B and L. J Neurochem 67: 1846-1855.
    [65] Grune T, Botzen D, Engels M, et al. (2010) Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions. Arch Biochem Biophys 500: 181-188. doi: 10.1016/
    [66] Petrucelli L, Dickson D, Kehoe K, et al. (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13: 703-714. doi: 10.1093/hmg/ddh083
    [67] Ulrich HD (2005) Mutual interactions between the SUMO and ubiquitin systems: a plea of no contest. Trends Cell Biol 15: 525-532. doi: 10.1016/j.tcb.2005.08.002
    [68] Morishima-Kawashima M, Hasegawa M, Takio K, et al. (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10: 1151-1160. doi: 10.1016/0896-6273(93)90063-W
    [69] Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2: 492-501. doi: 10.1038/35081564
    [70] Polymeropoulos MH, Lavedan C, Leroy E, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047. doi: 10.1126/science.276.5321.2045
    [71] Krüger R, Kuhn W, Müller T, et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18: 106-108. doi: 10.1038/ng0298-106
    [72] Zarranz JJ, Alegre J, Gómez-Esteban JC, et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55: 164-173. doi: 10.1002/ana.10795
    [73] Spillantini MG, Goedert M (2000) The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci ;920: 16-27.
    [74] Weinreb PH, Zhen W, Poon AW, et al. (1996) NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35: 13709-13715. doi: 10.1021/bi961799n
    [75] Iwai A, Masliah E, Yoshimoto M, et al. (1995) The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14: 467-475. doi: 10.1016/0896-6273(95)90302-X
    [76] Iwata A, Maruyama M, Kanazawa I, et al. (2001) alpha-Synuclein affects the MAPK pathway and accelerates cell death. J Biol Chem 276: 45320-45329. doi: 10.1074/jbc.M103736200
    [77] Chandra S, Fornai F, Kwon H-B, et al. (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A 101: 14966-14971. doi: 10.1073/pnas.0406283101
    [78] Chandra S, Gallardo G, Fernández-Chacón R, et al. (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123: 383-396. doi: 10.1016/j.cell.2005.09.028
    [79] Liu S, Ninan I, Antonova I, et al. (2004) alpha-Synuclein produces a long-lasting increase in neurotransmitter release. EMBO J 23: 4506-4516. doi: 10.1038/sj.emboj.7600451
    [80] Liu S, Fa M, Ninan I, et al. (2007) Alpha-synuclein involvement in hippocampal synaptic plasticity: role of NO, cGMP, cGK and CaMKII. Eur J Neurosci 25: 3583-3596. doi: 10.1111/j.1460-9568.2007.05569.x
    [81] Spillantini MG, Schmidt ML, Lee VM, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839-840. doi: 10.1038/42166
    [82] Kahle PJ, Neumann M, Ozmen L, et al. (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3: 583-588. doi: 10.1093/embo-reports/kvf109
    [83] Barghorn S, Davies P, Mandelkow E (2004) Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain. Biochemistry 43: 1694-1703. doi: 10.1021/bi0357006
    [84] Conway KA, Harper JD, Lansbury PT (2000) Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 39: 2552-2563. doi: 10.1021/bi991447r
    [85] Serpell LC, Berriman J, Jakes R, et al. (2000) Fiber diffraction of synthetic alpha -synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci U S A 97: 4897-4902. doi: 10.1073/pnas.97.9.4897
    [86] Okochi M, Walter J, Koyama A, et al. (2000) Constitutive Phosphorylation of the Parkinson's Disease Associated -Synuclein. J Biol Chem 275: 390-397. doi: 10.1074/jbc.275.1.390
    [87] Smith WW, Margolis RL, Li X, et al. (2005) Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25: 5544-5552. doi: 10.1523/JNEUROSCI.0482-05.2005
    [88] Giasson BI (2000) Oxidative Damage Linked to Neurodegeneration by Selective alpha -Synuclein Nitration in Synucleinopathy Lesions. Science 290: 985-989. doi: 10.1126/science.290.5493.985
    [89] Hodara R, Norris EH, Giasson BI, et al. (2004) Functional consequences of alpha-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. J Biol Chem 279: 47746-47753. doi: 10.1074/jbc.M408906200
    [90] Anderson JP, Walker DE, Goldstein JM, et al. (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281: 29739-29752. doi: 10.1074/jbc.M600933200
    [91] Bennett MC, Bishop JF, Leng Y, et al. (1999) Degradation of -Synuclein by Proteasome. J Biol Chem 274: 33855-33858. doi: 10.1074/jbc.274.48.33855
    [92] Lee JT, Wheeler TC, Li L, et al. (2008) Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 17: 906-917.
    [93] Kim YM, Jang WH, Quezado MM, et al. (2011) Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation. J Neurol Sci 307: 157-161. doi: 10.1016/j.jns.2011.04.015
    [94] Krumova P, Meulmeester E, Garrido M, et al. (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol 194: 49-60. doi: 10.1083/jcb.201010117
    [95] Iwatsubo T, Yamaguchi H, Fujimuro M, et al. (1996) Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol 148: 1517-1529.
    [96] Iwatsubo T (2003) Aggregation of alpha-synuclein in the pathogenesis of Parkinson's disease. J Neurol 250 Suppl : III11-4.
    [97] Nonaka T, Iwatsubo T, Hasegawa M (2005) Ubiquitination of alpha-synuclein. Biochemistry 44: 361-368. doi: 10.1021/bi0485528
    [98] Pountney DL, Voelcker NH, Gai WP (2005) Annular alpha-synuclein oligomers are potentially toxic agents in alpha-synucleinopathy. Hypothesis. Neurotox Res 7: 59-67. doi: 10.1007/BF03033776
    [99] Oh Y, Kim YM, Mouradian MM, et al. (2011) Human Polycomb protein 2 promotes α-synuclein aggregate formation through covalent SUMOylation. Brain Res 1381: 78-89. doi: 10.1016/j.brainres.2011.01.039
    [100] Matic I, van Hagen M, Schimmel J, et al. (2008) In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy. Mol Cell Proteomics 7: 132-144.
    [101] Sapetschnig A, Rischitor G, Braun H, et al. (2002) Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO J 21: 5206-5215. doi: 10.1093/emboj/cdf510
    [102] Shahpasandzadeh H, Popova B, Kleinknecht A, et al. (2014) Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions. J Biol Chem 289: 31224-31240. doi: 10.1074/jbc.M114.559237
    [103] Kunadt M, Eckermann K, Stuendl A, et al. (2015) Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation. Acta Neuropathol 129: 695-713. doi: 10.1007/s00401-015-1408-1
    [104] Yuan B-Z, Chapman JA, Reynolds SH (2008) Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells. Transl Oncol 1: 129-140. doi: 10.1593/tlo.08133
    [105] Xie W, Li X, Li C, et al. (2010) Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease. J Neurochem 115: 188-199. doi: 10.1111/j.1471-4159.2010.06914.x
    [106] Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6: 743-755.
    [107] Margolis RL, Ross CA (2001) Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases. Trends Mol Med 7: 479-482. doi: 10.1016/S1471-4914(01)02179-7
    [108] MacDonald ME, Barnes G, Srinidhi J, et al. (1993) Gametic but not somatic instability of CAG repeat length in Huntington's disease. J Med Genet 30: 982-986. doi: 10.1136/jmg.30.12.982
    [109] Cattaneo E (2001) Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci 24: 182-188. doi: 10.1016/S0166-2236(00)01721-5
    [110] Ross CA (1995) When more is less: Pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15: 493-496. doi: 10.1016/0896-6273(95)90138-8
    [111] Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552-1555. doi: 10.1126/science.292.5521.1552
    [112] Poirier MA, Li H, Macosko J, et al. (2002) Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J Biol Chem 277: 41032-41037. doi: 10.1074/jbc.M205809200
    [113] Steffan JS, Agrawal N, Pallos J, et al. (2004) SUMO modification of Huntingtin and Huntington's disease pathology. Science 304: 100-104. doi: 10.1126/science.1092194
    [114] Tobin AJ, Signer ER (2000) Huntington's disease: the challenge for cell biologists. Trends Cell Biol 10: 531-536. doi: 10.1016/S0962-8924(00)01853-5
    [115] Ellerby LM, Hackam AS, Propp SS, et al. (2002) Kennedy's Disease. J Neurochem 2: 185-195.
    [116] Li H, Li SH, Johnston H, et al. (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25: 385-389. doi: 10.1038/78054
    [117] Toneff T, Mende-Mueller L, Wu Y, et al. (2002) Comparison of huntingtin proteolytic fragments in human lymphoblast cell lines and human brain. J Neurochem 82: 84-92. doi: 10.1046/j.1471-4159.2002.00940.x
    [118] Lunkes A, Lindenberg KS, Ben-Haïem L, et al. (2002) Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell 10: 259-269. doi: 10.1016/S1097-2765(02)00602-0
    [119] Warby SC, Doty CN, Graham RK, et al. (2008) Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet 17: 2390-2404. doi: 10.1093/hmg/ddn139
    [120] Davies SW, Turmaine M, Cozens BA, et al. (1997) Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation. Cell 90: 537-548. doi: 10.1016/S0092-8674(00)80513-9
    [121] Kalchman MA, Graham RK, Xia G, et al. (1996) Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J Biol Chem 271: 19385-19394 doi: 10.1074/jbc.271.32.19385
    [122] Ehrnhoefer DE, Sutton L, Hayden MR (2011) Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17: 475-492. doi: 10.1177/1073858410390378
    [123] Pennuto M, Palazzolo I, Poletti A (2009) Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity. Hum Mol Genet 18: R40-47. doi: 10.1093/hmg/ddn412
    [124] Zheng Z, Diamond MI (2012) Huntington disease and the huntingtin protein. Prog Mol Biol Transl Sci 107: 189-214. doi: 10.1016/B978-0-12-385883-2.00010-2
    [125] Cummings CJ, Zoghbi HY (2000) Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet 9: 909-916. doi: 10.1093/hmg/9.6.909
    [126] Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, et al. (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408: 101-106. doi: 10.1038/35040584
    [127] Saudou F, Finkbeiner S, Devys D, et al. (1998) Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions. Cell 95: 55-66. doi: 10.1016/S0092-8674(00)81782-1
    [128] Tsai YC, Fishman PS, Thakor N V, et al. (2003) Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem 278: 22044-22055. doi: 10.1074/jbc.M212235200
    [129] Donaldson KM, Li W, Ching KA, et al. (2003) Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci U S A 100: 8892-8897. doi: 10.1073/pnas.1530212100
    [130] Desterro JM, Rodriguez MS, Hay RT (1998) SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell 2: 233-239. doi: 10.1016/S1097-2765(00)80133-1
    [131] Hoege C, Pfander B, Moldovan G-L, et al. (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419: 135-141. doi: 10.1038/nature00991
    [132] Lin X, Liang M, Liang Y-Y, et al. (2003) SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem 78: 31043-31048.
    [133] Lee DH, Goldberg AL (1998) Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol 8: 397-403. doi: 10.1016/S0962-8924(98)01346-4
    [134] Tatham MH, Matic I, Mann M, et al. (2011) Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci Signal 4: rs4.
    [135] Janer A, Werner A, Takahashi-Fujigasaki J, et al. (2010) SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7. Hum Mol Genet 19: 181-195. doi: 10.1093/hmg/ddp478
    [136] Ryu J, Cho S, Park BC, et al. (2010) Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: Implication of JNK pathway. Biochem Biophys Res Commun 393: 280-285. doi: 10.1016/j.bbrc.2010.01.122
    [137] Zhou Y-F, Liao S-S, Luo Y-Y, et al. (2013) SUMO-1 modification on K166 of polyQ-expanded ataxin-3 strengthens its stability and increases its cytotoxicity. PLoS One 8: e54214. doi: 10.1371/journal.pone.0054214
    [138] Almeida B, Abreu IA, Matos CA, et al. (2015) SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97. Biochim Biophys Acta 1852: 1950-1959. doi: 10.1016/j.bbadis.2015.06.010
    [139] Thompson LM, Aiken CT, Kaltenbach LS, et al. (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 187: 1083-1099. doi: 10.1083/jcb.200909067
    [140] Browne SE, Beal MF (2006) Oxidative damage in Huntington's disease pathogenesis. Antioxid Redox Signal 8: 2061-2073. doi: 10.1089/ars.2006.8.2061
    [141] Saitoh H, Hinchey J (2000) Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 275: 6252-6258. doi: 10.1074/jbc.275.9.6252
    [142] O'Rourke JG, Gareau JR, Ochaba J, et al. (2013) SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 4: 362-375. doi: 10.1016/j.celrep.2013.06.034
    [143] Atwal RS, Truant R (2008) A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy. Autophagy 4: 91-93. doi: 10.4161/auto.5201
    [144] Rockabrand E, Slepko N, Pantalone A, et al. (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16: 61-77.
    [145] Sivanandam VN, Jayaraman M, Hoop CL, et al. (2011) The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils. J Am Chem Soc 133: 4558-4566. doi: 10.1021/ja110715f
    [146] Zheng Z, Li A, Holmes BB, et al. (2013) An N-terminal nuclear export signal regulates trafficking and aggregation of Huntingtin (Htt) protein exon 1. J Biol Chem 288: 6063-6071. doi: 10.1074/jbc.M112.413575
    [147] Alefantis T, Barmak K, Harhaj EW, et al. (2003) Characterization of a nuclear export signal within the human T cell leukemia virus type I transactivator protein Tax. J Biol Chem 278: 21814-21822. doi: 10.1074/jbc.M211576200
    [148] Sipione S, Rigamonti D, Valenza M, et al. (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum Mol Genet 11: 1953-1965. doi: 10.1093/hmg/11.17.1953
    [149] Graham RK, Deng Y, Slow EJ, et al. (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125: 1179-1191. doi: 10.1016/j.cell.2006.04.026
    [150] Schmidt D, Müller S (2002) Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci U S A 99: 2872-2877. doi: 10.1073/pnas.052559499
    [151] Steffan JS, Bodai L, Pallos J, et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739-743. doi: 10.1038/35099568
    [152] Marsh JL, Thompson LM (2006) Drosophila in the study of neurodegenerative disease. Neuron 52: 169-178. doi: 10.1016/j.neuron.2006.09.025
    [153] Subramaniam S, Sixt KM, Barrow R, et al. (2009) Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324: 1327-1330. doi: 10.1126/science.1172871
    [154] Rosen DR, Siddique T, Patterson D, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59-62. doi: 10.1038/362059a0
    [155] Andersen PM (2006) Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr Neurol Neurosci Rep 6: 37-46. doi: 10.1007/s11910-996-0008-9
    [156] Cleveland DW (1999) From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron 24: 515-520. doi: 10.1016/S0896-6273(00)81108-3
    [157] Rabizadeh S, Gralla EB, Borchelt DR, et al. (1995) Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells. Proc Natl Acad Sci U S A 92: 3024-3028. doi: 10.1073/pnas.92.7.3024
    [158] Takeuchi H, Kobayashi Y, Ishigaki S, et al. (2002) Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis. J Biol Chem 277: 50966-50972. doi: 10.1074/jbc.M209356200
    [159] Guégan C, Vila M, Teismann P, et al. (2002) Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS. Mol Cell Neurosci 20: 553-562. doi: 10.1006/mcne.2002.1136
    [160] Bruijn LI, Houseweart MK, Kato S, et al. (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281: 1851-11854.
    [161] Son M, Cloyd CD, Rothstein JD, et al. (2003) Aggregate formation in Cu,Zn superoxide dismutase-related proteins. J Biol Chem 278: 14331-14336. doi: 10.1074/jbc.M211698200
    [162] Watanabe M, Dykes-Hoberg M, Culotta VC, et al. (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8: 933-941. doi: 10.1006/nbdi.2001.0443
    [163] Lin H, Zhai J, Schlaepfer WW (2005) RNA-binding protein is involved in aggregation of light neurofilament protein and is implicated in the pathogenesis of motor neuron degeneration. Hum Mol Genet 14: 3643-3659. doi: 10.1093/hmg/ddi392
    [164] Howland DS, Liu J, She Y, et al. (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 99: 1604-1609. doi: 10.1073/pnas.032539299
    [165] Fei E, Jia N, Yan M, et al. (2006) SUMO-1 modification increases human SOD1 stability and aggregation. Biochem Biophys Res Commun 347: 406-412. doi: 10.1016/j.bbrc.2006.06.092
    [166] Niikura T, Kita Y, Abe Y (2014) SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants. PLoS One 9: e101080. doi: 10.1371/journal.pone.0101080
    [167] Cashman NR, Durham HD, Blusztajn JK, et al. (1992) Neuroblastoma x spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev Dyn 194: 209-221. doi: 10.1002/aja.1001940306
    [168] Buschmann T, Fuchs SY, Lee CG, et al. (2000) SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 101: 753-762. doi: 10.1016/S0092-8674(00)80887-9
    [169] Obata Y, Niikura T, Kanekura K, et al. (2005) Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity. J Neurosci Res 81: 72072-72079.
    [170] Woo C-H, Abe J-I (2010) SUMO--a post-translational modification with therapeutic potential? Curr Opin Pharmacol 10: 146-155. doi: 10.1016/j.coph.2009.12.001
    [171] Su H-L, Li SS-L. (2002) Molecular features of human ubiquitin-like SUMO genes and their encoded proteins. Gene 296: 65-73. doi: 10.1016/S0378-1119(02)00843-0
    [172] Tempé D, Piechaczyk M, Bossis G (2008) SUMO under stress. Biochem Soc Trans 36: 874-878. doi: 10.1042/BST0360874
    [173] Parakh S, Spencer DM, Halloran MA, et al. (2013) Redox regulation in amyotrophic lateral sclerosis. Oxid Med Cell Longev 2013: 408681.
    [174] Nakamura T, Cho D-H, Lipton SA (2012) Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases. Exp Neurol 238: 12-21. doi: 10.1016/j.expneurol.2012.06.032
    [175] Wang H-Y, Wang I-F, Bose J, et al. (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83: 130-139. doi: 10.1016/S0888-7543(03)00214-3
    [176] Mercado PA, Ayala YM, Romano M, et al. (2005) Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 33: 6000-6010. doi: 10.1093/nar/gki897
    [177] Buratti E, Dörk T, Zuccato E, et al. (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20: 1774-1784. doi: 10.1093/emboj/20.7.1774
    [178] Strong MJ, Volkening K, Hammond R, et al. (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35: 320-327. doi: 10.1016/j.mcn.2007.03.007
    [179] Arai T, Hasegawa M, Akiyama H, et al. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611. doi: 10.1016/j.bbrc.2006.10.093
    [180] Neumann M, Sampathu DM, Kwong LK, et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-133. doi: 10.1126/science.1134108
    [181] Cairns NJ, Neumann M, Bigio EH, et al. (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171: 227-240. doi: 10.2353/ajpath.2007.070182
    [182] Forman MS, Trojanowski JQ, Lee VM-Y (2007) TDP-43: a novel neurodegenerative proteinopathy. Curr Opin Neurobiol 17: 548-555. doi: 10.1016/j.conb.2007.08.005
    [183] Kim SH, Shanware NP, Bowler MJ, et al. (2010) Amyotrophic Lateral Sclerosis-associated Proteins TDP-43 and FUS/TLS Function in a Common Biochemical Complex to Co-regulate HDAC6 mRNA. J Biol Chem 285: 34097-34105. doi: 10.1074/jbc.M110.154831
    [184] Rutherford NJ, Zhang Y-J, Baker M, et al. (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4: e1000193. doi: 10.1371/journal.pgen.1000193
    [185] Johnson BS, McCaffery JM, Lindquist S, et al. (2008) A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci U S A 105: 6439-6444. doi: 10.1073/pnas.0802082105
    [186] Zhang Y-J, Xu Y-F, Cook C, et al. (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A 106: 7607-7612. doi: 10.1073/pnas.0900688106
    [187] Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl: S10-17.
    [188] Davidson Y, Kelley T, Mackenzie IRA, et al. (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113: 521-533. doi: 10.1007/s00401-006-0189-y
    [189] Taylor JP (2002) Toxic Proteins in Neurodegenerative Disease. Science 296: 1991-1995. doi: 10.1126/science.1067122
    [190] Dewey CM, Cenik B, Sephton CF, et al. (2012) TDP-43 aggregation in neurodegeneration: are stress granules the key? Brain Res 1462: 16-25. doi: 10.1016/j.brainres.2012.02.032
    [191] Fang Y-S, Tsai K-J, Chang Y-J, et al. (2014) Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat Commun 5: 4824. doi: 10.1038/ncomms5824
    [192] Colby DW, Prusiner SB (2011) Prions. Cold Spring Harb Perspect Biol 3: a006833.
    [193] Nonaka T, Masuda-Suzukake M, Arai T, et al. (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4: 124-134. doi: 10.1016/j.celrep.2013.06.007
    [194] Guo W, Chen Y, Zhou X, et al. (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol18: 822-830.
    [195] Hasegawa M, Arai T, Nonaka T, et al. (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64: 60-70. doi: 10.1002/ana.21425
    [196] Igaz LM, Kwong LK, Xu Y, et al. (2008) Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol 173: 182-194. doi: 10.2353/ajpath.2008.080003
    [197] Igaz LM, Kwong LK, Chen-Plotkin A, et al. (2009) Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. J Biol Chem 284: 8516-8524. doi: 10.1074/jbc.M809462200
    [198] Wegorzewska I, Bell S, Cairns NJ, et al. (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 106: 18809-18814. doi: 10.1073/pnas.0908767106
    [199] Wils H, Kleinberger G, Janssens J, et al. (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 107: 3858-3863. doi: 10.1073/pnas.0912417107
    [200] Xu Y-F, Gendron TF, Zhang Y-J, et al. (2010) Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci 30: 10851-10859. doi: 10.1523/JNEUROSCI.1630-10.2010
    [201] Zhou H, Huang C, Chen H, et al. (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6: e1000887. doi: 10.1371/journal.pgen.1000887
    [202] Sreedharan J, Blair IP, Tripathi VB, et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668-1672. doi: 10.1126/science.1154584
    [203] Van Deerlin VM, Leverenz JB, Bekris LM, et al. (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7: 409-416. doi: 10.1016/S1474-4422(08)70071-1
    [204] Kabashi E, Valdmanis PN, Dion P, et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40: 572-574. doi: 10.1038/ng.132
    [205] Seyfried NT, Gozal YM, Dammer EB, et al. (2010) Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics 9: 705-718. doi: 10.1074/mcp.M800390-MCP200
    [206] Mann M (2006) Functional and quantitative proteomics using SILAC. Nat Rev Mol Cell Biol 7: 952-958.
    [207] Olsen J V, Blagoev B, Gnad F, et al. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127: 635-648. 208. doi: 10.1016/j.cell.2006.09.026
    [208] Liu R, Yang G, Nonaka T, et al. (2013) Reducing TDP-43 aggregation does not prevent its cytotoxicity. Acta Neuropathol Commun 1: 49. doi: 10.1186/2051-5960-1-49
  • Reader Comments
  • © 2015 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (
通讯作者: 陈斌,
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索


Article views(3583) PDF downloads(1621) Cited by(8)

Article outline

Figures and Tables



DownLoad:  Full-Size Img  PowerPoint