Advertisement

The Ubiquitin–Proteasome System in Synapses

  • Suzanne Tydlacka
  • Shi-Hua Li
  • Xiao-Jiang Li
Chapter

Abstract

The ubiquitin–proteasome system (UPS) is responsible for clearing most soluble proteins in the cytoplasm and nucleus. Recent studies reveal that the UPS function is critical for maintaining synaptic plasticity and transmission and that the UPS dysfunction is associated with axonal degeneration and impaired synaptic transmission. In this chapter, we will focus on the role of the UPS in synapses and the association of UPS impairment with neurological disorders. Since protein misfolding causes several neurological disorders that show synaptic dysfunction during the early stages of disease, understanding the involvement of the synaptic UPS in neurological disorders may help determine effective strategies for treating neurological disorders caused by the accumulation of misfolded proteins.

Keywords

Presynaptic Terminal Synaptic Dysfunction Mutant Huntingtin polyQ Disease polyQ Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aguilera M, Oliveros M, Martinez-Padron M, Barbas JA, and Ferrus A (2000) Aridne-1: a vital Drosophila gene is required in development and defines a new conserved family of ring-finger proteins. Genetics 155:1231–1244PubMedGoogle Scholar
  2. Bence NF, Sampat RM, and Kopito RR (2001) Impairment of the ubiquitin–proteasome system by protein aggregation. Science 292:1552–1555CrossRefPubMedGoogle Scholar
  3. Bennett EJ, Bence NF, Jayakumar R, and Kopito RR (2005) Global impairment of the ubiquitin–proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17:351–365CrossRefPubMedGoogle Scholar
  4. Bennett EJ, Shaler TA, Woodman B, Ryu KY, Zaitseva TS, Becker CH, Bates GP, Schulman H, and Kopito RR (2007) Global changes to the ubiquitin system in Huntington’s disease. Nature 448:704–708CrossRefPubMedGoogle Scholar
  5. Bett JS, Goellner GM, Woodman B, Pratt G, Rechsteiner M, and Bates GP (2006) Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington’s disease mouse: exclusion of proteasome activator REGγ as a therapeutic target. Hum Mol Genet 15:33–44CrossRefPubMedGoogle Scholar
  6. Bingol B and Schuman EM (2005) Synaptic protein degradation by the ubiquitin proteasome system. Curr Opin Neurobiol 15:536–541CrossRefPubMedGoogle Scholar
  7. Bloom AJ, Miller BR, Sanes JR, and DiAntonio A (2007) The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons. Genes Dev 21:2593–2606CrossRefPubMedGoogle Scholar
  8. Bowman AB, Yoo SY, Dantuma, NP and Zoghbi HY (2005) Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin–proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 14:679–691CrossRefPubMedGoogle Scholar
  9. Campbell DS and Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026CrossRefPubMedGoogle Scholar
  10. Chau V, Tobias JW, Bachmar A, Marriott D, Ecker DJ, Gonda DK, and Varshavsky A (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243:1576–1583CrossRefPubMedGoogle Scholar
  11. Chen H, Polo S, Fiore PP, and Camilli PV (2003) Rapid Ca2+-dependent decrease of protein ubiquitination at synapses. Proc Natl Acad Sci U S A 100:14908–14913CrossRefPubMedGoogle Scholar
  12. Ciechanover A (1998) The ubiquitin–proteasome pathway: on protein death and cell life. EMBO 17:7151–7160CrossRefGoogle Scholar
  13. Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6:79–87CrossRefPubMedGoogle Scholar
  14. Ciechanover A and Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446CrossRefPubMedGoogle Scholar
  15. Colamarino CY and Tessier-Lavigne M (1995) The axonal chemoattractant netrin-1 is also a chemorepellent for trochlear motor axons. Cell 81:621–629CrossRefPubMedGoogle Scholar
  16. Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, Lu H, Bear MF, and Scott JD (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40:595–607CrossRefPubMedGoogle Scholar
  17. Conforti L, Tarlton A, Mack TG, Mi W, Buckmaster EA, Wagner D, Perry VH, and Coleman MP (2000) A Ufd2/D4cole1e chimeric protein and overexperssion of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci U S A 97:11377–11382CrossRefPubMedGoogle Scholar
  18. Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, and Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19:148–154CrossRefPubMedGoogle Scholar
  19. Cummings CJ, Reinstein E, Sun Y, Antalffy B, Jiang Y, Ciehanoer A, Orr HT, Beaudet AL, and Zoghbi HY (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24:879–892CrossRefPubMedGoogle Scholar
  20. DiAntonio A, Haghighi AP, Portman SL, Lee JD, Amaranto AM, and Goodman CS (2001) Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412:449–452CrossRefPubMedGoogle Scholar
  21. Díaz-Hernández M, Hernández F, Martín-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, Ferrer I, Avila J, and Lucas JJ (2003) Neuronal induction of the immunoproteasome in Huntington’s disease. J Neurosci 23:11653–11661PubMedGoogle Scholar
  22. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, and Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993CrossRefPubMedGoogle Scholar
  23. Dobie F and Craig AM (2007) A fight for neurotransmission: SCRAPPER trashes RIM. Cell 130:775–777CrossRefPubMedGoogle Scholar
  24. Ehlers MD (2003) Activity levels controls postsynaptic composition and signaling via the ubiquitin–proteasome system. Nat Neurosci 6:231–242CrossRefPubMedGoogle Scholar
  25. Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F. (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118:127–138Google Scholar
  26. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899CrossRefPubMedGoogle Scholar
  27. Gutekunst CA, Li SH, Yi H, Ferrante RJ, Li XJ, and Hersch SM (1998) The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. J Neurosci 18:7674–7686PubMedGoogle Scholar
  28. Haas KF, Miller SLH, Friedman DB, and Broadie K (2007) The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function. Mol Cell Neurosci 35:64–75CrossRefPubMedGoogle Scholar
  29. Huang Y, Baker RT, and Fischer-Vize JA (1995) Control of cell fate by a deubiquitinating enzyme encoded by the fat facets gene. Science 270:1828–1831CrossRefPubMedGoogle Scholar
  30. Jana NR, Zemskov EA, Wang G, and Nukina N (2001) Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 10:1049–1059CrossRefPubMedGoogle Scholar
  31. Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi-Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, Gietz RD, and Hayden MR (1997) HIP, a human homologue of S. cerevisiae S1a2p, interacts with membrain-associated huntingtin in the brain. Nat Genet 16:44–53CrossRefPubMedGoogle Scholar
  32. Kopito RR (2000) Aggregosmes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530CrossRefPubMedGoogle Scholar
  33. Layfield R, Cavey JR, and Lowe J (2003) Role of ubiquitin-mediated proteolysis in the pathogenesis of neurodegenerative disorders. Ageing Res Rev 2:343–356CrossRefPubMedGoogle Scholar
  34. Li SH and Li XJ (2004) Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 20:146–154CrossRefPubMedGoogle Scholar
  35. Li XJ, Li SH, Sharp AH, Nucifora FC Jr, Schilling G, Lanahan A, Worley P, Snyder SH, and Ross CA (1995) A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378:398–402CrossRefPubMedGoogle Scholar
  36. Li H, Li SH, Cheng AL, Mangiarini L, Bates GP, and Li XJ (1999) Ultrastructural localization and progressive formation of neuropil aggregates in Huntington’s disease transgenic mice. Hum Mol Genet 8:1227–1236CrossRefPubMedGoogle Scholar
  37. Li H, Li SH, Johnston H, Shelbourne PF, and Li XJ (2000a) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25:385–389CrossRefPubMedGoogle Scholar
  38. Li SH, Li H, Torre ER, and Li XJ (2000b) Expression of huntingtin-associated protein-1 in neuronal cells implicates a role in neurite growth. Mol Cell Neuroscience 16:168–183CrossRefGoogle Scholar
  39. Li KW, Hornshaw MP, Van Der Schors RC, Watson R, Tate S, Casetta B, Jimenez CR, Gouwenberg Y, Gundelfinger ED, and Smalla KW (2004) Proteomics analysis of rat brain postsynaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. J Biol Chem 279:987–1002CrossRefPubMedGoogle Scholar
  40. Lindsten K, Menendez-Benito V, Masucci MG, and Dantuma NP (2003) A transgenic mouse model of the ubiquitin/proteasome system. Nat Biotechnol 21:897–902CrossRefPubMedGoogle Scholar
  41. Martin KA, Poeck B, Roth H, Ebens AJ, Ballard LC, and Zipursky SL (1995) Mutations disrupting neuronal connectivity in the Drosophila visual system. Neuron 14:229–240CrossRefPubMedGoogle Scholar
  42. Mayer AN and Wilkinson KD (1989) Detection, resolution, and nomenclature of multiple ubiquitin carboxyl-terminal esterases from bovine calf thymus. Biochemistry 28:166–172CrossRefPubMedGoogle Scholar
  43. Muralidhar MG and Thomas JB (1993) The Drosophila bendless gene encodes a neural protein related to ubiquitin-conjugating enzymes. Neuron 11:253–266CrossRefPubMedGoogle Scholar
  44. Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ. (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci. 28:2783–2792Google Scholar
  45. Orr HT and Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621CrossRefPubMedGoogle Scholar
  46. Pak DT and Sheng M (2003) Targeted protein degradation and synpase remodeling by an inducible protein kinase. Science 302:1368–1373CrossRefPubMedGoogle Scholar
  47. Patrick GN (2006) Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system. Curr Opin Neurobiol 16:90–94CrossRefPubMedGoogle Scholar
  48. Patrick GN, Bingol B, Weld HA, and Schuman EM (2003) Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs. Curr Biol 13:2073–2081CrossRefPubMedGoogle Scholar
  49. Pickart CM and Cohen RE (2004) Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Dev Biol 5:177–187CrossRefGoogle Scholar
  50. Poeck B, Fischer S, Gunning D, Zipursky SL, and Salecker I (2001) Glial cells mediate target layer selection of retinal axons in the developing visual system of Drosophila. Neuron 29:99–113CrossRefPubMedGoogle Scholar
  51. Saigoh K, Wang YL, Suh T, Yamanishi Y, Sakai H, Kiyosawa T, Harada N, Ichihara S, Wakana T, Kikuchi, and Wada K (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23:47–51PubMedGoogle Scholar
  52. Schaefer AM, Hadwiger GD, and Nonet ML (2000) RPM-1, a conserved neuronal gene that regulates targeting and synaptogenesis in C. elegans. Neuron 26:345–356CrossRefPubMedGoogle Scholar
  53. Skinner PJ, Vierra-Green CA, Clark HB, Zoghbi HY, and Orr HT (2001) Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic mice. Am J Pathol 159:905–913CrossRefPubMedGoogle Scholar
  54. Smith R, Brudin P, and Li JY (2005) Synaptic dysfunction in Huntington’s disease: a new perspective. Cell Mol Life Sci 62:1901–1912CrossRefPubMedGoogle Scholar
  55. Trushina E, Dyer RB, Badger JD 2nd, Ure D, Eide L, Tran DD, Vrieze BT, Legendre-Guillemin V, McPherson PS, Mandavilli BS, Van Houten B, Zeitlin S, McNiven M, Aebersold R, Hayden M, Parisi JE, Seeberg E, Dragatsis I, Doyle K, Bender A, Chacko C, McMurray CT (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24:8195–8209Google Scholar
  56. Tydlacka S, Wang CE, Wang X, Li SH, and Li XJ (2008) Differential activities of the ubiquitin–proteasome system in neurons versus glia may account for the preferential accumulation of misfolded proteins in neurons. J Neurosci 28:13285–13295CrossRefPubMedGoogle Scholar
  57. Usdin MT, Shelbourne PF, Myers RM, and Madison DV (1999) Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet 8:839–946CrossRefPubMedGoogle Scholar
  58. Uthaman SB, Godenschwege TA, and Murphey RK (2008) A mechanism distinct from highwire for the drosophila ubiquitin conjugase bendless in synaptic growth and maturation. J Neursci 28:8615–8623CrossRefGoogle Scholar
  59. Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL. (2004) Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 14:95–104Google Scholar
  60. Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, and Wanker EE (2001) Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 12:1393–1407PubMedGoogle Scholar
  61. Wan HI, DiAntonio A, Fetter RD, Bergstrom K, Strauss R, and Goodman CS (2000) Highwire regulates synaptic growth in Drosophila. Neuron 26:313–329CrossRefPubMedGoogle Scholar
  62. Wang JJ, Wang CE, Orr A, Tydlacka S, Li Sh, and Li XJ (2008a) Impaired ubiquitin–proteasome system activity in the synapses of Huntington’s disease mice. J Cell Biol 180:1177–1189CrossRefPubMedGoogle Scholar
  63. Wang CE, Tydlacka S, Orr AL, Yang SH, Graham RK, Hayden MR, Li S, Chan AW, and Li XJ (2008b) Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease. Hum Mol Genet 17:2738–2751CrossRefPubMedGoogle Scholar
  64. Willeumier K, Pulst SM, and Schweizer FE (2006) Proteasome inhibition triggers activity-dependent increase in size of the recycling vesicle pool in cultured hippocampal neurons. 26:11333–11341Google Scholar
  65. Wilson SM, Bhattacharyya B, Rachel RA, Coppola V, Tessarollo L, Householder DB, Fletcher CF, Miller RJ, Copeland NG, and Jenkins NA (2002) Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat Genet 32:420–425CrossRefPubMedGoogle Scholar
  66. Wolf DH and Hilt W (2004) The proteasome: a proteolytic nanomachine of cell regulation and waste disposal. Biochim Biophys Acta 1695:19–31CrossRefPubMedGoogle Scholar
  67. Yao I, Takagi H, Ageta H, Kahyo T, Sato S, Hatanaka K, Fukauda Y, Chiba T, Morone N, Yuasa S, Inokuchi K, Ohtsuka T, MacGregor GR, Tanaka K, and Setou M (2007) SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. Cell 130:943–957CrossRefPubMedGoogle Scholar
  68. Yu ZX, Li SH, Evans J, Pillarisetti A, Li H, Li XJ. (2003) Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington’s disease. J Neurosci. 23:2193-202Google Scholar
  69. Yi JJ and Ehlers MD (2005) Ubiquitin and protein turnover in synapse formation. Neuron 47:629–632CrossRefPubMedGoogle Scholar
  70. Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L, and He Z (2003) Involvement of the ubiquitin–proteasome system in the early stages of wallerian degeneration. Neuron 39:217–225CrossRefPubMedGoogle Scholar
  71. Zhou H, Cao F, Wang Z, Yu ZX, Nguyen HP, Evans J, Li SH, and Li XJ (2003) Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J Cell Biol 163:109–118CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Human GeneticsEmory University School of MedicineAtlantaUSA

Personalised recommendations