The roles of intracellular protein-degradation pathways in neurodegeneration


Many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease, are associated with the formation of intracellular aggregates by toxic proteins. It is therefore crucial to understand the factors that regulate the steady-state levels of these 'toxins', at both the synthetic and degradation stages. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin–proteasome system and macroautophagy. Dysfunction of the ubiquitin–proteasome or macroautophagy pathways might contribute to the pathology of various neurodegenerative conditions. However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases.

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Figure 1: Schematic diagram of the ubiquitin–proteasome system.
Figure 2: Macroautophagy as a default pathway for proteasome-inaccessible substrates.
Figure 3: Removal of aggregates can occur through removal of their precursors.


  1. 1

    Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Ross, C. A. & Poirier, M. A. What is the role of protein aggregation in neurodegeneration? Nature Rev. Mol. Cell Biol. 6, 891–898 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Perutz, M. F. & Windle, A. H. Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature 412, 143–144 (2001).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Pangalos, M. N., Jacobsen, S. J. & Reinhart, P. H. Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the β-amyloid peptide. Biochem. Soc. Trans. 33, 553–558 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Wellington, C. L. et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J. Neurosci. 22, 7862–7872 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Luo, S., Vacher, C., Davies, J. E. & Rubinsztein, D. C. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J. Cell Biol. 169, 647–656 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Wellington, C. L. et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158–9167 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Ciechanover, A. The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology 66, S7–S19 (2006).

    Article  Google Scholar 

  9. 9

    Richly, H. et al. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73–84 (2005).

    CAS  Article  Google Scholar 

  10. 10

    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  Article  Google Scholar 

  11. 11

    Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Verhoef, L. G., Lindsten, K., Masucci, M. G. & Dantuma, N. P. Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum. Mol. Genet. 11, 2689–2700 (2002).

    CAS  Article  Google Scholar 

  14. 14

    Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N. & Goldberg, A. L. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol. Cell 14, 95–104 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Holmberg, C. I., Staniszewski, K. E., Mensah, K. N., Matouschek, A. & Morimoto, R. I. Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J. 23, 4307–4318 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Yorimitsu, T. & Klionsky, D. J. Autophagy: molecular machinery for self-eating. Cell Death Differ. 12, 1542–1552 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Shibata, M. et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474–14485 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Iwata, A. et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc. Natl Acad. Sci. USA 102, 13135–13140 (2005).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Qin, Z. H. et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum. Mol. Genet. 12, 3231–3244 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Ravikumar, B. et al. mTOR inhibition induces autophagy and reduces toxicity of the Huntington's disease mutation in Drosophila and mouse models. Nature Genet. 36, 585–595 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Ravikumar, B. et al. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum. Mol. Genet. 12, 985–994 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Rideout, H., Lang-Rollin, I. & Stefanis, L. Involvement of macroautophagy in the dissolution of neuronal inclusions. Int. J. Biochem. Cell Biol. 36, 2551–2562 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Massey, A., Kiffin, R. & Cuervo, A. M. Pathophysiology of chaperone-mediated autophagy. Int. J. Biochem. Cell Biol. 36, 2420–2434 (2004).

    CAS  Article  Google Scholar 

  26. 26

    McNaught, K. S., Belizaire, R., Isacson, O., Jenner, P. & Olanow, C. W. Altered proteasomal function in sporadic Parkinson's disease. Exp. Neurol. 179, 38–46 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Seo, H., Sonntag, K. C. & Isacson, O. Generalized brain and skin proteasome inhibition in Huntington's disease. Ann. Neurol. 56, 319–328 (2004).

    CAS  Article  Google Scholar 

  28. 28

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

    ADS  CAS  Article  Google Scholar 

  29. 29

    Bowman, A. B., Yoo, S. Y., Dantuma, N. P. & Zoghbi, H. Y. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin–proteasome system impairment and inversely correlates with a degree of nuclear inclusion formation. Hum. Mol. Genet. 14, 679–691 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Diaz-Hernandez, M. et al. Neuronal induction of the immunoproteasome in Huntington's disease. J. Neurosci. 23, 11653–11661 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Sun, X. M. et al. Caspase activation inhibits proteasome function during apoptosis. Mol. Cell 14, 81–93 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Zhang, Y. et al. Parkin functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl Acad. Sci. USA 97, 13354–13359 (2000).

    ADS  CAS  Article  Google Scholar 

  33. 33

    Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin–protein ligase. Nature Genet. 25, 302–305 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Imai, Y., Soda, M. & Takahashi, R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin–protein ligase activity. J. Biol. Chem. 275, 35661–35664 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Leroy, E. et al. The ubiquitin pathway in Parkinson's disease. Nature 395, 451–452 (1998).

    ADS  CAS  Article  Google Scholar 

  36. 36

    Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57–87 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Healy, D. G. et al. UCHL-1 is not a Parkinson's disease susceptibility gene. Ann. Neurol. 59, 627–633 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T. 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  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

  40. 40

    Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genet. 36, 377–381 (2004).

    CAS  Article  Google Scholar 

  41. 41

    McNaught, K. S., Perl, D. P., Brownell, A. L. & Olanow, C. W. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann. Neurol. 56, 149–162 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    ADS  CAS  Article  Google Scholar 

  43. 43

    Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025–1040 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Ravikumar, B., Berger, Z., Vacher, C., O'Kane, C. J. & Rubinsztein, D. C. Rapamycin pre-treatment protects against apoptosis. Hum. Mol. Genet. 15, 1209–1216 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    ADS  CAS  Article  Google Scholar 

  46. 46

    Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    ADS  CAS  Article  Google Scholar 

  47. 47

    Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature Genet. 37, 771–776 (2005).

    CAS  Article  Google Scholar 

  48. 48

    Levy, J. R. et al. A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation. J. Cell Biol. 172, 733–745 (2006).

    CAS  Article  Google Scholar 

  49. 49

    Puls, I. et al. Mutant dynactin in motor neuron disease. Nature Genet. 33, 455–456 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Hafezparast, M. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808–812 (2003).

    ADS  CAS  Article  Google Scholar 

  51. 51

    Kieran, D. et al. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J. Cell Biol. 169, 561–567 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Ligon, L. A. et al. Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons. Neuroreport 16, 533–536 (2005).

    CAS  Article  Google Scholar 

  53. 53

    Cuervo, A. M., Stefansi, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    ADS  CAS  Article  Google Scholar 

  54. 54

    Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005).

    ADS  CAS  Article  Google Scholar 

  55. 55

    Rodriguez-Lebron, E. & Paulson, H. L. Allele-specific RNA interference for neurological disease. Gene. Ther. 13, 576–581 (2006).

    CAS  Article  Google Scholar 

  56. 56

    Davies, J. E., Sarkar, S. & Rubinsztein, D. C. Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy. Hum. Mol. Genet. 15, 23–31 (2006).

    CAS  Article  Google Scholar 

  57. 57

    Sanchez, I., Mahlke, C. & Yuan, Y. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003).

    ADS  CAS  Article  Google Scholar 

  58. 58

    Martin-Aparicio, E. et al. Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease. J. Neurosci. 21, 8772–8781 (2001).

    CAS  Article  Google Scholar 

  59. 59

    Yamamoto, A., Cremona, M. L. & Rothman, J. E. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).

    CAS  Article  Google Scholar 

  60. 60

    DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    CAS  Article  Google Scholar 

  61. 61

    Kiffin, R., Bandyopadhyay, U. & Cuervo, A. Oxidative stress and autophagy. Antioxid. Redox Signal. 8, 152–162 (2006).

    CAS  Article  Google Scholar 

  62. 62

    Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).

    ADS  CAS  Article  Google Scholar 

  63. 63

    Lee, V. W. & Chapman, J. R. Sirolimus: its role in nephrology. Nephrology (Carlton) 10, 606–614 (2005).

    CAS  Article  Google Scholar 

  64. 64

    Bjornsti, M. A. & Houghton, P. J. The TOR pathway: a target for cancer therapy. Nature Rev. Cancer 4, 335–348 (2004).

    Article  Google Scholar 

  65. 65

    Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).

    CAS  Article  Google Scholar 

  66. 66

    Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

    CAS  Article  Google Scholar 

  67. 67

    Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111 (2005).

    CAS  Article  Google Scholar 

  68. 68

    Murphy, M. P. How understanding the control of energy metabolism can help investigation of mitochondrial dysfunction, regulation and pharmacology. Biochim. Biophys. Acta 1504, 1–11 (2001).

    CAS  Article  Google Scholar 

  69. 69

    Pyo, J. et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J. Biol. Chem. 280, 20722–20728 (2005).

    CAS  Article  Google Scholar 

  70. 70

    Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioural and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

    CAS  Article  Google Scholar 

  71. 71

    Zeitlin, S. et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homolog. Nature Genet. 11, 155–163 (1995).

    CAS  Article  Google Scholar 

  72. 72

    Duyao, M. P. et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269, 407–410 (1995).

    ADS  CAS  Article  Google Scholar 

  73. 73

    Harper, P. S. Huntington's Disease 2nd edn (WB Saunders, London, 1996).

    Google Scholar 

  74. 74

    Rubinsztein, D. C. Lessons from animal models of Huntington's disease. Trends Genet. 18, 202–209 (2002).

    CAS  Article  Google Scholar 

  75. 75

    Ordway, J. M. et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91, 753–763 (1997).

    CAS  Article  Google Scholar 

  76. 76

    Cattaneo, E., Zuccato, C. & Tartari, M. Normal huntingtin function: an alternative approach to Huntington's disease. Nature Rev. Neurosci. 6, 919–930 (2005).

    CAS  Article  Google Scholar 

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I am grateful to B. Ravikumar and M. Futter for critical comments on the manuscript and L. Smith for help with manuscript preparation. The work in my laboratory covered by this review has been funded by a Wellcome Trust Senior Fellowship in Clinical Science, a Medical Research Council (MRC) Programme Grant, Wyeth, and European Union Framework VI (EUROSCA).

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D.C.R. is an inventor on patents relating to the use of autophagy induction for treating neurodegenerative diseases. His laboratory has received grant funding from Wyeth, which makes rapamycins.

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

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