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Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction

Key Points

  • In neurons as well as other eukaryotic cells, intracellular proteins are primarily degraded by the ubiquitin–proteasome system (UPS), and membrane proteins by the lysosome system. Ubiquitylation tags proteins for proteasomal degradation and vesicular trafficking.

  • Protein degradation is important for synaptic plasticity and self-renewal of neurons. The UPS can regulate presynaptic processes such as vesicle release and postsynaptic processes such as glutamate receptor turnover and postsynaptic density (PSD) reorganization.

  • Many neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, are characterized by aggregates in the brain of ubiquitin-positive proteins that failed to be degraded. PARK2 (which encodes the E3 ligase parkin) mutations lead to familial Parkinson's disease, suggesting that degradative dysfunction can trigger neurodegeneration. Mutations in many UPS and lysosomal genes are now linked to neurological disorders.

  • The morphology of neurons creates special demands for protein degradation with respect to membrane-protein turnover and substrate delivery to proteolytic machineries. This may explain why neurons are more susceptible to protein aggregation when protein degradation is impaired.

  • Protein degradation in axons and dendrites exhibits several unique features, including long-range retrograde transport of endocytosed proteins and the translocation of proteasomes into dendritic spines.

  • Various UPS components, including E3 ligases, deubiquitylating enzymes, chaperones, shuttling factors and different subtypes of proteasomes, form complex interaction networks in neurons. We know that individual components can have important functions, but detailed mechanisms remain elusive.

  • Enhancing protein degradation in the brain is a potential therapeutic strategy for aggregate-related neurodegenerative disorders. Another possibility is to enhance molecular chaperones that prevent protein misfolding.

Abstract

Eukaryotic protein degradation by the proteasome and the lysosome is a dynamic and complex process in which ubiquitin has a key regulatory role. The distinctive morphology of the postmitotic neuron creates unique challenges for protein degradation systems with respect to cell-surface protein turnover and substrate delivery to proteolytic machineries that are required for both synaptic plasticity and self-renewal. Moreover, the discovery of ubiquitin-positive protein aggregates in a wide spectrum of neurodegenerative diseases underlines the importance and vulnerability of the degradative system in neurons. In this article, we discuss the molecular mechanism of protein degradation in the neuron with respect to both its function and its dysfunction.

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Figure 1: The UPS.
Figure 2: Lysosomal pathways.
Figure 3: Aplysia LTF: regulation of PKA by the UPS.
Figure 4: Proteasome structure and heterogeneity.
Figure 5: Degradation of synaptic proteins.

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References

  1. Ciechanover, A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Exp. Biol. Med. 231, 1197–1211 (2006).

    Google Scholar 

  2. Ciechanover, A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nature Rev. Mol. Cell. Biol. 6, 79–86 (2005).

    CAS  Google Scholar 

  3. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Schoenheimer, R. The Dynamic State of Body Constituents (Harvard Univ. Press, Cambridge, Massachusetts, 1942).

    Google Scholar 

  5. Simpson, M. V. The release of labeled amino acids from the proteins of rat liver slices. J. Biol. Chem. 201, 143–154 (1953).

    CAS  PubMed  Google Scholar 

  6. Goldberg, A. L. Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem. Soc. Trans. 35, 12–17 (2007).

    CAS  PubMed  Google Scholar 

  7. Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell. Dev. Biol. 19, 141–172 (2003).

    CAS  PubMed  Google Scholar 

  8. Steward, O. & Schuman, E. M. Compartmentalized synthesis and degradation of proteins in neurons. Neuron 40, 347–359 (2003).

    CAS  PubMed  Google Scholar 

  9. Bingol, B. & Schuman, E. M. Synaptic protein degradation by the ubiquitin proteasome system. Curr. Opin. Neurobiol. 15, 536–541 (2005).

    CAS  PubMed  Google Scholar 

  10. Yi, J. J. & Ehlers, M. D. Emerging roles for ubiquitin and protein degradation in neuronal function. Pharmacol. Rev. 59, 14–39 (2007).

    CAS  PubMed  Google Scholar 

  11. DiAntonio, A. & Hicke, L. Ubiquitin-dependent regulation of the synapse. Annu. Rev. Neurosci. 27, 223–246 (2004).

    CAS  PubMed  Google Scholar 

  12. Murphey, R. K. & Godenschwege, T. A. New roles for ubiquitin in the assembly and function of neuronal circuits. Neuron 36, 5–8 (2002).

    CAS  PubMed  Google Scholar 

  13. Patrick, G. N. Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system. Curr. Opin. Neurobiol. 16, 90–94 (2006).

    CAS  PubMed  Google Scholar 

  14. Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nature Med. 10, S10–S17 (2004).

    PubMed  Google Scholar 

  15. Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780–786 (2006).

    CAS  PubMed  Google Scholar 

  16. Nakatsukasa, K., Huyer, G., Michaelis, S. & Brodsky, J. L. Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132, 101–112 (2008). This study showed that transmembrane proteins at the ER can be degraded by the proteasome, which is assisted by multiple chaperones.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Luzio, J. P., Pryor, P. R. & Bright, N. A. Lysosomes: fusion and function. Nature Rev. Mol. Cell. Biol. 8, 622–632 (2007).

    CAS  Google Scholar 

  18. Pillay, C. S., Elliott, E. & Dennison, C. Endolysosomal proteolysis and its regulation. Biochem. J. 363, 417–429 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, New York, 1949).

    Google Scholar 

  20. Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559 (1984).

    CAS  PubMed  Google Scholar 

  21. Lopez-Salon, M. et al. The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur. J. Neurosci. 14, 1820–1826 (2001). This study demonstrated that the blockade of protein degradation can cause memory impairment in rodents.

    CAS  PubMed  Google Scholar 

  22. Lee, S. H. et al. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256 (2008).

    CAS  PubMed  Google Scholar 

  23. Hegde, A. N., Goldberg, A. L. & Schwartz, J. H. Regulatory subunits of cAMP-dependent protein kinase are degraded after conjugation to ubiquitin: a molecular mechanism underlying long-term synaptic plasticity. Proc. Natl Acad. Sci. USA 90, 7436–7440 (1993). A pioneering study on the role of protein degradation in long-term synaptic plasticity in Aplysia , focusing on the cAMP–PKA–CREB pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Byrne, J. H. & Kandel, E. R. Presynaptic facilitation revisited: state and time dependence. J. Neurosci. 16, 425–35 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chain, D. G. et al. Mechanisms for generating the autonomous cAMP-dependent protein kinase required for long-term facilitation in Aplysia. Neuron 22, 147–156 (1999).

    CAS  PubMed  Google Scholar 

  26. Hegde, A. N. et al. Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell 89, 115–126 (1997).

    CAS  PubMed  Google Scholar 

  27. Hegde, A. N. & DiAntonio, A. Ubiquitin and the synapse. Nature Rev. Neurosci. 3, 854–861 (2002).

    CAS  Google Scholar 

  28. Zhao, Y. L., Hegde, A. N. & Martin, K. C. The ubiquitin proteasome system functions as an inhibitory constraint on synaptic strengthening. Curr. Biol. 13, 887–898 (2003).

    CAS  PubMed  Google Scholar 

  29. Fonseca, R., Vabulas, R. M., Hartl, F. U., Bonhoeffer, T. & Nagerl, U. V. A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245 (2006).

    CAS  PubMed  Google Scholar 

  30. Karpova, A., Mikhaylova, M., Thomas, U., Knopfel, T. & Behnisch, T. Involvement of protein synthesis and degradation in long-term potentiation of Schaffer collateral CA1 synapses. J. Neurosci. 26, 4949–4955 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Krug, M., Lossner, B. & Ott, T. Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39–42 (1984).

    CAS  PubMed  Google Scholar 

  32. Willeumier, K., Pulst, S. M. & Schweizer, F. E. Proteasome inhibition triggers activity-dependent increase in the size of the recycling vesicle pool in cultured hippocampal neurons. J. Neurosci. 26, 11333–11341 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Yao, I. et al. SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. Cell 130, 943–957 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).

    CAS  PubMed  Google Scholar 

  35. Ehlers, M. D. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neurosci. 6, 231–242 (2003). A careful study on the bidirectional regulation of PSD composition by neuronal activity, highlighting the role of proteasomal degradation in synaptic remodelling.

    CAS  PubMed  Google Scholar 

  36. Ding, Q., Cecarini, V. & Keller, J. N. Interplay between protein synthesis and degradation in the CNS: physiological and pathological implications. Trends Neurosci. 30, 31–36 (2007).

    CAS  PubMed  Google Scholar 

  37. Lowe, J., Mayer, R. J. & Landon, M. Ubiquitin in neurodegenerative diseases. Brain Pathol. 3, 55–65 (1993).

    CAS  PubMed  Google Scholar 

  38. Chung, K. K., Dawson, V. L. & Dawson, T. M. The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders. Trends Neurosci. 24, S7–S14 (2001).

    CAS  PubMed  Google Scholar 

  39. Gómez-Tortosa, E., Irizarry, M. C., Gómez-Isla, T. & Hyman, B. T. Clinical and neuropathological correlates of dementia with Lewy bodies. Ann. NY Acad. Sci. 920, 9–15 (2000).

    PubMed  Google Scholar 

  40. Lennox, G. et al. Diffuse Lewy body disease: correlative neuropathology using anti-ubiquitin immunocytochemistry. J. Neurol. Neurosurg. Psychiatr. 52, 1236–1247 (1989).

    CAS  Google Scholar 

  41. Bugiani, O. The many ways to frontotemporal degeneration and beyond. Neurol. Sci. 28, 241–244 (2007).

    CAS  PubMed  Google Scholar 

  42. Cummings, J. L. Dementia with Lewy bodies: molecular pathogenesis and implications for classification. J. Geriatr. Psychiatry Neurol. 17, 112–119 (2004).

    PubMed  Google Scholar 

  43. Mayer, R. J. et al. Endosome-lysosomes, ubiquitin and neurodegeneration. Adv. Exp. Med. Biol. 389, 261–269 (1996).

    CAS  PubMed  Google Scholar 

  44. Anderson, J. P. et al. Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739–29752 (2006). A proteomic study of Lewy bodies from PD and DLB patients that reveal the phosphorylation state and ubiquitylation state of α-synuclein.

    CAS  PubMed  Google Scholar 

  45. Thrower, J. S., Hoffman, L., Rechsteiner, M. & Pickart, C. M. Recognition of the polyubiquitin proteolytic signal. EMBO J. 19, 94–102 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Dahlmann, B. Role of proteasomes in disease. BMC Biochem. 8 (Suppl. 1), S3 (2007).

    PubMed  PubMed Central  Google Scholar 

  47. Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555 (2001).

    CAS  PubMed  Google Scholar 

  48. Wang, J. et al. Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice. J. Cell Biol. 180, 1177–1189 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lansbury, P. T. & Lashuel, H. A. A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443, 774–779 (2006).

    CAS  PubMed  Google Scholar 

  50. Kakizuka, A. Roles of VCP in human neurodegenerative disorders. Biochem. Soc. Trans. 36, 105–108 (2008).

    CAS  PubMed  Google Scholar 

  51. McNaught, K. S. P., Olanow, C. W., Halliwell, B., Isacson, O. & Jenner, P. Failure of the ubiquitin-proteasome system in Parkinson's disease. Nature Rev. Neurosci. 2, 589–594 (2001).

    CAS  Google Scholar 

  52. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shacka, J. J., Roth, K. A. & Zhang, J. The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy. Front. Biosci. 13, 718–736 (2008).

    CAS  PubMed  Google Scholar 

  54. Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).

    CAS  PubMed  Google Scholar 

  55. Belin, A. C. & Westerlund, M. Parkinson's disease: a genetic perspective. FEBS J. 275, 1377–1383 (2008).

    CAS  PubMed  Google Scholar 

  56. von Coelln, R., Dawson, V. L. & Dawson, T. M. Parkin-associated Parkinson's disease. Cell Tissue Res. 318, 175–184 (2004).

    PubMed  Google Scholar 

  57. Pankratz, N. & Foroud, T. Genetics of Parkinson disease. Genet. Med. 9, 801–811 (2007).

    PubMed  Google Scholar 

  58. Ichihara, N. et al. Axonal degeneration promotes abnormal accumulation of amyloid β-protein in ascending gracile tract of Gracile Axonal Dystrophy (GAD) mouse. Brain Res. 695, 173–178 (1995).

    CAS  PubMed  Google Scholar 

  59. Saigoh, K. et al. Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nature Genet. 23, 47–51 (1999).

    CAS  PubMed  Google Scholar 

  60. Case, A. & Stein, R. L. Mechanistic studies of ubiquitin C-terminal hydrolase L1. Biochemistry 45, 2443–2452 (2006).

    CAS  PubMed  Google Scholar 

  61. Gould, E. How widespread is adult neurogenesis in mammals? Nature Rev. Neurosci. 8, 481–488 (2007).

    CAS  Google Scholar 

  62. Terman, A. & Brunk, U. T. Is aging the price for memory? Biogerontology 6, 205–210 (2005). An interesting discussion on the evolutionary tradeoff between aging neurons and stable memory, and the involvement of protein degradation.

    PubMed  Google Scholar 

  63. Major, G., Larkman, A. U., Jonas, P., Sakmann, B. & Jack, J. J. B. Detailed passive cable model of whole-cell recorded CA3 pyramidal neurons in rat hippocampal slices. J. Neurosci. 14, 4613–4638 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Marsh, J. L. & Thompson, L. M. Drosophila in the study of neurodegenerative disease. Neuron 52, 169–178 (2006).

    CAS  PubMed  Google Scholar 

  65. Semple, C. A. M. The comparative proteomics of ubiquitination in mouse. Genome Res. 13, 1389–1394 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ardley, H. C. & Robinson, P. A. E3 ubiquitin ligases. Essays Biochem. 41, 15–30 (2005).

    CAS  PubMed  Google Scholar 

  67. Kaiser, P. & Huang, L. Global approaches to understanding ubiquitination. Genome Biol. 6, 2331–2338 (2005).

    Google Scholar 

  68. Moore, D. J. Parkin: a multifaceted ubiquitin ligase. Biochem. Soc. Trans. 34, 749–753 (2006).

    CAS  PubMed  Google Scholar 

  69. Brooks, C. L. & Gu, W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21, 307–315 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ding, M., Chao, D., Wang, G. & Shen, K. Spatial regulation of an E3 ubiquitin ligase directs selective synapse elimination. Science 317, 947–951 (2007).

    CAS  PubMed  Google Scholar 

  71. Jiang, Y. H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998).

    CAS  PubMed  Google Scholar 

  72. Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B. & Beaudet, A. L. The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum. Mol. Genet. 17, 111–118 (2008).

    CAS  PubMed  Google Scholar 

  73. Lalande, M. & Calciano, M. A. Molecular epigenetics of Angelman syndrome. Cell. Mol. Life Sci. 64, 947–960 (2007).

    CAS  PubMed  Google Scholar 

  74. Zenker, M. et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nature Genet. 37, 1345–1350 (2005).

    CAS  PubMed  Google Scholar 

  75. Ganesh, S., Puri, R., Singh, S., Mittal, S. & Dubey, D. Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J. Hum. Genet. 51, 1–8 (2006).

    CAS  PubMed  Google Scholar 

  76. Tarpey, P. S. 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. 80, 345–352 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Field, M. et al. Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly. Am. J. Hum. Genet. 81, 367–374 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Froyen, G. et al. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am. J. Hum. Genet. 82, 432–443 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Olzmann, J. A. et al. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J. Cell Biol. 178, 1025–1038 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith, W. W. et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl Acad. Sci. USA 102, 18676–18681 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sakata, E. et al. Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep. 4, 301–306 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Dächsel, J. C. et al. Parkin interacts with the proteasome subunit α4. FEBS Lett. 579, 3913–3919 (2005).

    PubMed  Google Scholar 

  83. Wang, X. R. et al. Mass spectrometric characterization of the affinity-purified human 26S proteasome complex. Biochemistry 46, 3553–3565 (2007). The first proteomic characterization of affinity-purified proteasomes from mammalian cells.

    CAS  PubMed  Google Scholar 

  84. Wang, X. R. & Huang, L. Identifying dynamic interactors of protein complexes by quantitative mass spectrometry. Mol. Cell. Proteomics 7, 46–57 (2008).

    PubMed  Google Scholar 

  85. Henn, I. H., Gostner, J. M., Lackner, P., Tatzelt, J. & Winklhofer, K. F. Pathogenic mutations inactivate parkin by distinct mechanisms. J. Neurochem. 92, 114–122 (2005).

    CAS  PubMed  Google Scholar 

  86. Mouatt-Prigent, A. et al. Ultrastructural localization of parkin in the rat brainstem, thalamus and basal ganglia. J. Neural Transm. 111, 1209–1218 (2004).

    CAS  PubMed  Google Scholar 

  87. Kim, J. H., Park, K. C., Chung, S. S., Bang, O. & Chung, C. H. Deubiquitinating enzymes as cellular regulators. J. Biochem. 134, 9–18 (2003).

    CAS  PubMed  Google Scholar 

  88. Koulich, E., Li, X. & DeMartino, G. N. Relative structural and functional roles of multiple deubiquitylating proteins associated with mammalian 26S proteasome. Mol. Biol. Cell. 19, 1072–1082 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Anderson, C. et al. Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice. J. Neurochem. 95, 724–731 (2005).

    CAS  PubMed  Google Scholar 

  90. Wilson, S. M. et al. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nature Genet. 32, 420–425 (2002).

    CAS  PubMed  Google Scholar 

  91. Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T. Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell 111, 209–218 (2002).

    CAS  PubMed  Google Scholar 

  92. Dueñas, A. M., Goold, R. & Giunti, P. Molecular pathogenesis of spinocerebellar ataxias. Brain 129, 1357–1370 (2006).

    PubMed  Google Scholar 

  93. Wang, Q. Y., Li, L. Y. & Ye, Y. H. Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3. J. Cell Biol. 174, 963–971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Meusser, B., Hirsch, C., Jarosch, E. & Sommer, T. ERAD: the long road to destruction. Nature Cell Biol. 7, 766–772 (2005).

    CAS  PubMed  Google Scholar 

  95. Weihl, C. C., Dalal, S., Pestronk, A. & Hanson, P. I. Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum. Mol. Genet. 15, 189–199 (2006).

    CAS  PubMed  Google Scholar 

  96. Neumann, M. et al. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J. Neuropathol. Exp. Neurol. 66, 152–157 (2007).

    PubMed  Google Scholar 

  97. Halawani, D. & Latterich, M. p97: the cell's molecular purgatory? Mol. Cell. 22, 713–717 (2006).

    CAS  PubMed  Google Scholar 

  98. Dreveny, I. et al. p97 and close encounters of every kind: a brief review. Biochem. Soc. Trans. 32, 715–720 (2004).

    CAS  PubMed  Google Scholar 

  99. Yeung, H. O. et al. Insights into adaptor binding to the AAA protein p97. Biochem. Soc. Trans. 36, 62–67 (2008).

    CAS  PubMed  Google Scholar 

  100. Muchowski, P. J. & Wacker, J. L. Modulation of neurodegeneration by molecular chaperones. Nature Rev. Neurosci. 6, 11–22 (2005).

    CAS  Google Scholar 

  101. Arndt, V., Rogon, C. & Hohfeld, J. To be, or not to be—molecular chaperones in protein degradation. Cell. Mol. Life Sci. 64, 2525–2541 (2007).

    CAS  PubMed  Google Scholar 

  102. Hartmann-Petersen, R., Seeger, M. & Gordon, C. Transferring substrates to the 26S proteasome. Trends Biochem. Sci. 28, 26–31 (2003).

    CAS  PubMed  Google Scholar 

  103. Madura, K. Rad23 and Rpn10: perennial wallflowers join the melee. Trends Biochem. Sci. 29, 637–640 (2004).

    CAS  PubMed  Google Scholar 

  104. Hartmann-Petersen, R. & Gordon, C. Integral UBL domain proteins: a family of proteasome interacting proteins. Semin. Cell Dev. Biol. 15, 247–259 (2004).

    CAS  PubMed  Google Scholar 

  105. Bingol, B. & Schuman, E. M. Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441, 1144–1148 (2006). This study demonstrated the rapid translocation of proteasomes into dendritic spines on KCl-induced depolarization.

    CAS  PubMed  Google Scholar 

  106. Guo, L. & Wang, Y. Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. Neuroscience 145, 100–109 (2007).

    CAS  PubMed  Google Scholar 

  107. Bingol, B. & Schuman, E. M. A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis. Neuropharmacology 47, 755–763 (2004).

    CAS  PubMed  Google Scholar 

  108. Colledge, M. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40, 595–607 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Li, K. W. et al. Proteomics analysis of rat brain postsynaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. J. Biol. Chem. 279, 987–1002 (2004).

    CAS  PubMed  Google Scholar 

  110. Schmidt, M., Hanna, J., Elsasser, S. & Finley, D. Proteasome-associated proteins: regulation of a proteolytic machine. Biol. Chem. 386, 725–737 (2005).

    CAS  PubMed  Google Scholar 

  111. Verma, R. et al. Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11, 3425–3439 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, F. et al. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell 115, 715–725 (2003).

    CAS  PubMed  Google Scholar 

  113. Glickman, M. H. & Raveh, D. Proteasome plasticity. FEBS Lett. 579, 3214–3223 (2005).

    CAS  PubMed  Google Scholar 

  114. Dahlmann, B. Proteasomes. Essays Biochem. 41, 31–48 (2005).

    CAS  PubMed  Google Scholar 

  115. Rechsteiner, M. & Hill, C. P. Mobilizing the proteolytic machine: cell biological roles of proteasome activators and inhibitors. Trends Cell Biol. 15, 27–33 (2005).

    CAS  PubMed  Google Scholar 

  116. Tanahashi, N. et al. Hybrid proteasomes: induction by interferon-γ and contribution to ATP-dependent proteolysis. J. Biol. Chem. 275, 14336–14345 (2000). This study demonstrated the existence of hybrid proteasomes and used extensive immunoprecipitation reactions to quantify proteasome subtypes in HeLa cells.

    CAS  PubMed  Google Scholar 

  117. Shibatani, T. et al. Global organization and function of mammalian cytosolic proteasome pools: implications for PA28 and 19S regulatory complexes. Mol. Biol. Cell 17, 4962–4971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, X. T. et al. The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGγ proteasome. Cell 124, 381–392 (2006).

    CAS  PubMed  Google Scholar 

  119. Shringarpure, R., Grune, T. & Davies, K. J. A. Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells. Cell. Mol. Life Sci. 58, 1442–1450 (2001).

    CAS  PubMed  Google Scholar 

  120. Noda, C., Tanahashi, N., Shimbara, N., Hendil, K. B. & Tanaka, K. Tissue distribution of constitutive proteasomes, immunoproteasomes, and PA28 in rats. Biochem. Biophys. Res. Commun. 277, 348–354 (2000).

    CAS  PubMed  Google Scholar 

  121. Pratt, G. & Rechsteiner, M. Proteasomes cleave at multiple sites within polyglutamine tracts: activation by PA28γ(K188E). J. Biol. Chem. 283, 12919–12925 (2008). This study showed that PA28 has the potential to facilitate the proteasomal degradation of polyQ aggregates.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Minami, Y. et al. A critical role for the proteasome activator PA28 in the Hsp90-dependent protein refolding. J. Biol. Chem. 275, 9055–9061 (2000).

    CAS  PubMed  Google Scholar 

  123. Poppek, D. & Grune, T. Proteasomal defense of oxidative protein modifications. Antioxid. Redox Signal. 8, 173–184 (2006).

    CAS  PubMed  Google Scholar 

  124. Burbea, M., Dreier, L., Dittman, J. S., Grunwald, M. E. & Kaplan, J. M. Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans. Neuron 35, 107–120 (2002).

    CAS  PubMed  Google Scholar 

  125. Rezvani, K., Teng, Y., Shim, D. & De Biasi, M. Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. J. Neurosci. 27, 10508–10519 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Kato, A., Rouach, N., Nicoll, R. A. & Bredt, D. S. Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination. Proc. Natl Acad. Sci. USA 102, 5600–5605 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Patrick, G. N., Bingol, B., Weld, H. A. & Schuman, E. M. Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs. Curr. Biol. 13, 2073–2081 (2003).

    CAS  PubMed  Google Scholar 

  128. Racz, B., Blanpied, T. A., Ehlers, M. D. & Weinberg, R. J. Lateral organization of endocytic machinery in dendritic spines. Nature Neurosci. 7, 917–918 (2004).

    CAS  PubMed  Google Scholar 

  129. Ehlers, M. D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).

    CAS  PubMed  Google Scholar 

  130. Lee, S. H., Simonetta, A. & Sheng, M. Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43, 221–236 (2004).

    CAS  PubMed  Google Scholar 

  131. Shepherd, J. D. & Huganir, R. L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell. Dev. Biol. 23, 613–643 (2007).

    CAS  PubMed  Google Scholar 

  132. Parton, R. G., Simons, K. & Dotti, C. G. Axonal and dendritic endocytic pathways in cultured neurons. J. Cell Biol. 119, 123–137 (1992). An informative study on endocytic and lysosomal pathways in axons and dendrites that used multiple techniques, including real-time imaging and electron microscopy.

    CAS  PubMed  Google Scholar 

  133. Walkley, S. U. in Neurobiology of Disease (ed. Gilman, S.) 1–18 (Elsevier, Burlington, 2007).

    Google Scholar 

  134. Walkley, S. U. Cellular pathology of lysosomal storage disorders. Brain Pathol. 8, 175–193 (1998).

    CAS  PubMed  Google Scholar 

  135. Settembre, C., Fraldi, A., Rubinsztein, D. C. & Ballabio, A. Lysosomal storage diseases as disorders of autophagy. Autophagy 4, 113–114 (2008).

    PubMed  Google Scholar 

  136. Holzbaur, E. L. F. Motor neurons rely on motor proteins. Trends Cell Biol. 14, 233–240 (2004).

    CAS  PubMed  Google Scholar 

  137. Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).

    CAS  PubMed  Google Scholar 

  138. Hunter, T. The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol. Cell 28, 730–738 (2007).

    CAS  PubMed  Google Scholar 

  139. Pak, D. T. & Sheng, M. Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science 302, 1368–1373 (2003).

    CAS  PubMed  Google Scholar 

  140. Neutzner, A., Youle, R. J. & Karbowski, M. Outer mitochondrial membrane protein degradation by the proteasome. Novartis Found. Symp. 287, 4–14 (2007).

    CAS  PubMed  Google Scholar 

  141. Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O. & Klionsky, D. J. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304–312 (2007).

    CAS  Google Scholar 

  142. Tanaka, M. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nature Med. 10, 148–154 (2004).

    CAS  PubMed  Google Scholar 

  143. Kuhlbrodt, K., Mouysset, J. & Hoppe, T. Orchestra for assembly and fate of polyubiquitin chains. Essays Biochem. 41, 1–14 (2005).

    CAS  PubMed  Google Scholar 

  144. Peng, J. M. et al. A proteomics approach to understanding protein ubiquitination. Nature Biotechnol. 21, 921–926 (2003). This study used mass spectrometry to demonstrate that all seven lysines on the ubiquitin can be used for polyubiquitin chain extension.

    CAS  Google Scholar 

  145. Mukhopadhyay, D. & Riezman, H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315, 201–205 (2007).

    CAS  PubMed  Google Scholar 

  146. Gruenberg, J. & Stenmark, H. The biogenesis of multivesicular endosomes. Nature Rev. Mol. Cell. Biol. 5, 317–323 (2004).

    CAS  Google Scholar 

  147. Nixon, R. A. & Cataldo, A. M. The endosomal-lysosomal system of neurons: new roles. Trends Neurosci. 18, 489–496 (1995).

    CAS  PubMed  Google Scholar 

  148. Dice, J. F. Chaperone-mediated autophagy. Autophagy 3, 295–299 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank C.-Y. Tai and Y. Yoon for manuscript suggestions and the support of the Howard Hughes Medical Institute.

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Glossary

Exergonic

An exergonic reaction is characterized by a negative change of overall Gibbs free energy. It is thermodynamically favourable and can occur spontaneously.

Ubiquitin

An 8.5 kD protein that is ubiquitously expressed in eukaryotic cells. The covalent modification of a protein by ubiquitin is called ubiquitination or ubiquitylation.

Synaptic plasticity

The ability of the synaptic connection between two neurons to change in strength.

Alzheimer's disease

(AD). The most common type of neurodegenerative dementia. Patients often show impairments in learning and memory. The disease's neuropathology includes neuron loss in the cerebral cortex and in some subcortical regions and the presence of aggregates in the forms of plaques (containing amyloid-β) and neurofibrillary tangles (containing hyperphosphorylated tau).

Parkinson's disease

(PD). A degenerative movement disorder that causes tremor and gait disturbance. The impairment of motor skills is caused by the loss of dopaminergic neurons in the substantia nigra, where deposits of Lewy bodies are found.

Autophagy

The breakdown of a cell's own components by the lysosome.

Retrograde amnesia

A form of amnesia in which the subject is unable to recall events that occurred before the onset of the amnesia or before the injurious event.

Inhibitory avoidance learning

In this learning paradigm, the animal prevents an aversive stimulus by suppressing a behaviour that is otherwise regularly shown in a particular environment. For instance, a rodent that received an electric foot shock for stepping off a platform learns to stay longer on the platform during test trials.

Long-term facilitation

(LTF). A type of long-lasting enhancement of synaptic transmission that is induced by specific neuronal activities and that was initially described in Aplysia. A similar process called long-term potentiation was first described in the mammalian hippocampus.

Aplysia

A marine snail, or sea slug, that has a simple nervous system that makes it a useful model organism for studying synaptic plasticity.

Immediate-early gene

A gene that is activated transiently and rapidly in response to cellular stimuli.

Ionotropic glutamate receptors

Glutamate receptors that exert their effects through the modulation of ion channel activity. In mammals they are classified into three major subtypes according to their agonist: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, NMDA (N-methyl-D-aspartate) receptors and kainate receptors.

Postsynaptic density

An electron-dense structure adjacent to the postsynaptic membrane, visible in electron micrographs, that contains receptor channels, structural proteins and signal transduction proteins.

Polyglutamine (PolyQ) expansion disease

Any genetic disease that results from expansions of CAG trinucleotide repeats, which are translated into lengthened polyQ regions that induce protein aggregation. Human polyQ diseases include HD, Kennedy's disease and spinocerebellar ataxias.

Lewy bodies

Protein aggregates that contain α-synuclein, ubiquitin and other proteins. They were first identified in PD and were later found to be present in other neurodegenerative diseases.

Dementia with Lewy bodies

(DLB). A prevalent type of late-onset dementia that is characterized by the presence of Lewy bodies distributed throughout limbic, paralimbic and neocortical regions.

Hydra

Small, fresh-water predatory animals with a simple body plan and radial symmetry. Hydras are model organisms for studying regeneration and body development.

Chaperone

A protein that assists the folding/unfolding and assembly/disassembly of other macromolecular structures.

Angelman syndrome

A neurogenetic disease that is caused by defects in the maternal copy of UBE3A (owing to genomic imprinting, the maternal copy of UBE3A is preferentially expressed in specific brain regions). The disease is characterized by brain growth retardation and jerky movements.

Johanson–Blizzard syndrome

A genetic disease that is characterized by pancreatic dysfunction, malformation and mental retardation. The disease is now linked to UBR1, which encodes an E3 ligase that selects substrates on the basis of their N-terminal residues.

Lafora's disease

A fatal genetic disorder that causes seizure, myoclonus and progressive dementia. Most cases are caused by mutations in EPM2A (which encodes laforin, a protein phosphatase) or NHLRC1 (which encodes malin, an E3 ligase).

Spinocerebellar ataxia

A class of genetic disorders that are characterized by slowly progressive incoordination of gait and that are often associated with poor coordination of hands, speech and eye movements.

Multivesicular body

At the ultrastructural level, a structure that appears as a large vesicle that contains multiple small vesicles. It can serve as the transport intermediate between early and late endosomes.

Degron

A specific part of a protein that is recognized by the degradative machinery as a proteolytic signal.

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Tai, HC., Schuman, E. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 9, 826–838 (2008). https://doi.org/10.1038/nrn2499

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