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Autophagy and neurodegeneration

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Abstract

All cellular components are subjected to continuous surveillance by intracellular quality control systems. The major players involved in this quality control are molecular chaperones, which detect the abnormal components, and proteases, which eliminate them from the cell. Malfunctioning of the cellular surveillance systems inexorably leads to cell toxicity, and often cell death, due to the accumulation of unwanted nonfunctional components inside cells. In this work, we review the contribution of the autophagic system to cellular quality control and the consequences that autophagy malfunction has on cellular function. Special emphasis is made on the recently identified role of this system in maintenance of neuronal homeostasis and in the links currently established between alterations in the autophagic system and major neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

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References and Recommended Reading

  1. Mizushima N: The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 2005, 12:1535–1541.

    Article  PubMed  CAS  Google Scholar 

  2. Yorimitsu T, Klionsky DJ: Autophagy: molecular machinery for self-eating. Cell Death Differ 2005, 12:1542–1552.

    Article  PubMed  CAS  Google Scholar 

  3. Cuervo A: Autophagy: in sickness and in health. Trends Cell Biol 2004, 14:70–77.

    Article  PubMed  CAS  Google Scholar 

  4. De Duve C, Wattiaux R: Functions of lysosomes. Ann Rev Physiol 1966, 28:435–492.

    Article  Google Scholar 

  5. Mortimore GE, Lardeux BR, Adams CE: Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation. J Biol Chem 1988, 263:2506–2512.

    PubMed  CAS  Google Scholar 

  6. Klionsky D, Cregg J, Dunn WJ, et al.: A unified nomenclature for yeast autophagy-related genes. Dev Cell 2003, 5:539–545.

    Article  PubMed  CAS  Google Scholar 

  7. Nixon R: Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci 2006, 29:528–535.

    Article  PubMed  CAS  Google Scholar 

  8. Dunn WJ: Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J Cell Biol 1990, 110:1935–1945.

    Article  PubMed  CAS  Google Scholar 

  9. Rodriguez-Enriquez S, He L, Lemasters J: Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol 2004, 36:2463–2472.

    Article  PubMed  CAS  Google Scholar 

  10. Iwata A, Christianson JC, Bucci M, et al.: Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci 2005, 102:13135–13140.

    Article  PubMed  CAS  Google Scholar 

  11. Bellu AR, Kiel JA: Selective degradation of peroxisomes in yeasts. Microsc Res Tech 2003, 61:161–170.

    Article  PubMed  CAS  Google Scholar 

  12. Massey A, Zhang C, Cuervo A: Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 2006, 73:205–235.

    Article  PubMed  CAS  Google Scholar 

  13. Majeski A, Dice J: Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 2004, 36:2435–2444.

    Article  PubMed  CAS  Google Scholar 

  14. Cuervo A, Dice J: A receptor for the selective uptake and degradation of proteins by lysosomes. Science 1996, 273:501–503.

    Article  PubMed  CAS  Google Scholar 

  15. Agarraberes F, Dice JF: A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci 2001, 114:2491–2499.

    PubMed  CAS  Google Scholar 

  16. Hara T, Nakamura K, Matsui M, et al.: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441:885–889.

    Article  PubMed  CAS  Google Scholar 

  17. Komatsu M, Waguri S, Chiba T, et al.: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006, 441:880–884.

    Article  PubMed  CAS  Google Scholar 

  18. Blommaart E, Lyiken J, Blommaart P, et al.: Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 1995, 270:2320–2326.

    Article  PubMed  CAS  Google Scholar 

  19. Ogier-Denis E, Codogno P: Autophagy: a barrier or an adaptative response to cancer. Biochim Biophys Acta 2003, 1603:113–128.

    PubMed  CAS  Google Scholar 

  20. Sarkar S, Davies J, Huang Z, et al.: Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and {alpha}-synuclein. J Biol Chem 2007, 282:5641–5652.

    Article  PubMed  CAS  Google Scholar 

  21. Sarkar S, Flot RA, Berger Z, et al.: Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005, 170:1101–1111.

    Article  PubMed  CAS  Google Scholar 

  22. Kiffin R, Christian C, Knecht E, Cuervo A: Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 2004, 15:4829–4840.

    Article  PubMed  CAS  Google Scholar 

  23. Cuervo A, Dice J: Regulation of lamp2a levels in the lysosomal membrane. Traffic 2000, 1:570–583.

    Article  PubMed  CAS  Google Scholar 

  24. Kaushik S, Massey AC, Cuervo AM: Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy. EMBO J 2006, 25:3921–3933.

    Article  PubMed  CAS  Google Scholar 

  25. Cheng J, Ohsaki Y, Tauchi-Sato K, et al.: Cholesterol depletion induces autophagy. Biochem Biophys Res Comm 2006, 351:246–252.

    Article  PubMed  CAS  Google Scholar 

  26. Deretic V: Autophagy as an immune defense mechanism. Curr Opin Immunol 2006, 18:375–382.

    Article  PubMed  CAS  Google Scholar 

  27. Kirkegaard K, Taylor M, Jackson W: Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol 2004, 2:301–314.

    Article  PubMed  CAS  Google Scholar 

  28. Nishino I: Autophagic vacuolar myopathies. Curr Neurol Neurosci Rep 2003, 3:64–69.

    Article  PubMed  Google Scholar 

  29. Fukuda T, Ewan L, Bauer M, et al.: Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 2006, 59:700–708.

    Article  PubMed  CAS  Google Scholar 

  30. Liang X, Jackson S, Seaman M, et al.: Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999, 402:672–676.

    Article  PubMed  CAS  Google Scholar 

  31. Kondo Y, Kanzawa T, Sawaya R, Kondo S: The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005, 5:726–734.

    Article  PubMed  CAS  Google Scholar 

  32. Cuervo AM, Bergamini E, Brunk UT, et al.: Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 2005, 1:131–140.

    PubMed  Google Scholar 

  33. Bergamini E: Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically. Mol Aspects Med 2006, 27:403–410.

    Article  PubMed  CAS  Google Scholar 

  34. Donati A, Cavallini G, Paradiso C, et al.: Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. J Gerontol A Biol Sci Med Sci 2001, 56:B288–293.

    PubMed  CAS  Google Scholar 

  35. Terman A: The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology 1995, 41:319–325.

    Article  PubMed  Google Scholar 

  36. Cuervo AM, Dice JF: Age-related decline in chaperonemediated autophagy. J Biol Chem 2000, 275:31505–31513.

    Article  PubMed  CAS  Google Scholar 

  37. Kiffin R, Kaushik S, Zeng M, et al.: Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci 2007, 120:782–791.

    Article  PubMed  CAS  Google Scholar 

  38. Lecker S, Goldberg A, Mitch W: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 2006, 17:1807–1819.

    Article  PubMed  CAS  Google Scholar 

  39. Finkbeiner S, Cuervo A, Morimoto R, Muchowski P: Diseasemodifying pathways in neurodegeneration. J Neurosci 2006, 26:10349–10357.

    Article  PubMed  CAS  Google Scholar 

  40. Cuervo AM, Stefanis L, Fredenburg R, et al.: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004, 305:1292–1295.

    Article  PubMed  CAS  Google Scholar 

  41. Gidalevitz T, Ben-Zvi A, Ho K, et al.: Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 2006, 311:1471–1474.

    Article  PubMed  CAS  Google Scholar 

  42. Salvador N, Aguado C, Horst M, Knecht E: Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J Biol Chem 2000, 275:27447–27456.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Iwata A, Riley BE, Johnston JA, Kopito RR: HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 2005, 280:40282–40292.

    Article  PubMed  CAS  Google Scholar 

  45. Nixon RA, Cataldo AM, Mathews PM: The endosomallysosomal system of neurons in Alzheimer’s disease pathogenesis: a review. Neurochem Res 2000, 25:1161–1172.

    Article  PubMed  CAS  Google Scholar 

  46. Nixon RA, Wegiel J, Kumar A, et al.: Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005, 64:113–122.

    PubMed  Google Scholar 

  47. Yu WH, Cuervo AM, Kumar A, et al.: Macroautophagy—a novel ta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 2005, 171:87–98.

    Google Scholar 

  48. Zheng L, Marcusson J, Terman A: Oxidative stress and Alzheimer disease: the autophagy connection? Autophagy 2006, 2:143–145.

    PubMed  CAS  Google Scholar 

  49. Lafay-Chebassier C, Paccalin CM, Page G, et al.: mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J Neurochem 2005, 94:215–225.

    Article  PubMed  CAS  Google Scholar 

  50. Nagatsu T, Swada M: Cellular and molecular mechanisms of Parkinson’s disease: neurotoxins, causative genes, and inflammatory cytokines. Cell Mol Neurobiol 2006, 26:781–802.

    Article  PubMed  CAS  Google Scholar 

  51. Stefanis L, Larsen KE, Rideout HJ, et al.: Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 2001, 21:9549–9560.

    PubMed  CAS  Google Scholar 

  52. Webb JL, Ravikumar B, Atkins J, et al.: Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003, 278:25009–25013.

    Article  PubMed  CAS  Google Scholar 

  53. Massey AC, Kaushik S, Sovak G, et al.: Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci USA 2006, 103:5905–5910.

    Article  CAS  Google Scholar 

  54. Kopito R: Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000, 10:523–530.

    Article  Google Scholar 

  55. Bjorkoy G, Lamark T, Brech A, et al.: p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005, 171:603–614.

    Article  PubMed  CAS  Google Scholar 

  56. Young AB: Huntingtin in health and disease. J Clin Invest 2003, 111:299–302.

    Article  PubMed  CAS  Google Scholar 

  57. Kegel K, Kim M, Sapp E, et al.: Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 2000, 20:7268–7278.

    PubMed  CAS  Google Scholar 

  58. Ravikumar B, Vacher C, Berger Z, et al.: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004, 36:585–595.

    Article  PubMed  CAS  Google Scholar 

  59. Qin ZH, Gu ZL: Huntingtin processing in pathogenesis of Huntington disease. Acta Pharmacol Sin 2004, 25:1243–1249.

    PubMed  CAS  Google Scholar 

  60. Shibata M, Lu T, Furuya T, et al.: Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 2006, 281:14474–14485.

    Article  PubMed  CAS  Google Scholar 

  61. Jia K, Hart AC, Levine B: Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. Autophagy 2007, 3:21–25.

    PubMed  CAS  Google Scholar 

  62. Ravikumar B, Berger Z, Vacher C, et al.: Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006, 15:1209–1216.

    Article  PubMed  CAS  Google Scholar 

  63. Debnath J, Baehrecke EH, Kroemer G: Does autophagy contribute to cell death? Autophagy 2005, 1:66–74.

    PubMed  CAS  Google Scholar 

  64. Pattingre S, Tassa A, Qu X, et al.: Bcl-2 Antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell 2005, 122:927–939.

    Article  PubMed  CAS  Google Scholar 

  65. Lum J, Bauer D, Kong M, et al.: Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005, 120:237–248.

    Article  PubMed  CAS  Google Scholar 

  66. Keller JN, Dimayuga E, Chen Q, et al.: Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol 2004, 36:2376–2391.

    Article  PubMed  CAS  Google Scholar 

  67. Contestabile A, Ciani E, Contestabile A: Dietary restriction differentially protects from neurodegeneration in animal models of excitotoxicity. Brain Res 2004, 1002:162–166.

    Article  PubMed  CAS  Google Scholar 

  68. Sarkar S, Perlstein E, Imarisio S, et al.: Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 2007, 3:331–338

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Ana Maria Cuervo.

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Ventruti, A., Cuervo, A.M. Autophagy and neurodegeneration. Curr Neurol Neurosci Rep 7, 443–451 (2007). https://doi.org/10.1007/s11910-007-0068-5

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