Neurosignals 2008;16:75–84
(DOI:10.1159/000109761)

The Role of Autophagy in Age-Related Neurodegeneration

McCray B.A. · Taylor J.P.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
email Corresponding Author


 goto top of outline Key Words

  • Autophagy
  • Neurodegeneration
  • Aging
  • Lysosome
  • Protein aggregation
  • Ubiquitin proteasome system

 goto top of outline Abstract

Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. In many cases, these proteinaceous deposits are composed of ubiquitin conjugates, suggesting a failure in the clearance of proteins targeted for degradation. The 2 principal routes of intracellular protein catabolism are the ubiquitin proteasome system and the autophagy-lysosome system (autophagy). Both of these degradation pathways have been implicated as playing important roles in the pathogenesis of neurodegenerative disease. Here we describe autophagy and review the evidence suggesting that impairment of autophagy contributes to the initiation or progression of age-related neurodegeneration. We also review recent evidence indicating that autophagy may be exploited to remove toxic protein species, suggesting novel strategies for therapeutic intervention for a class of diseases for which no effective treatments presently exist.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR: Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 2000;404:770–774.
  2. Taylor JP, Hardy J, Fischbeck KH: Toxic proteins in neurodegenerative disease. Science 2002;296:1991–1995.
  3. Muchowski PJ, Wacker JL: Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 2005;6:11–22.
  4. Rubinsztein DC: The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443:780–786.
  5. Ciechanover A: Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ 2005;12:1178–1190.
  6. Ciechanover A, Brundin P: The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 2003;40:427–446.
  7. Levine B, Klionsky DJ: Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004;6:463–477.
  8. Ahlberg J, Marzella L, Glaumann H: Uptake and degradation of proteins by isolated rat liver lysosomes: suggestion of a microautophagic pathway of proteolysis. Lab Invest 1982;47:523–532.
  9. Dunn WA Jr, Cregg JM, Kiel JA, van der Klei IJ, Oku M, Sakai Y, Sibirny AA, Stasyk OV, Veenhuis M: Pexophagy: the selective autophagy of peroxisomes. Autophagy 2005;1:75–83.
  10. Dice JF: Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 1990;15:305–309.
  11. Cuervo AM, Dice JF: A receptor for the selective uptake and degradation of proteins by lysosomes. Science 1996;273:501–503.
  12. Arstila AU, Trump BF: Studies on cellular autophagocytosis: the formation of autophagic vacuoles in the liver after glucagon administration. Am J Pathol 1968;53:687–733.
  13. Berg TO, Fengsrud M, Stromhaug PE, Berg T, Seglen PO: Isolation and characterization of rat liver amphisomes: evidence for fusion of autophagosomes with both early and late endosomes. J Biol Chem 1998;273:21883–21892.
  14. Martinez-Vicente M, Cuervo AM: Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 2007;6:352–361.
  15. Wang CW, Klionsky DJ: The molecular mechanism of autophagy. Mol Med 2003;9:65–76.
  16. Ohsumi Y: Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2001;2:211–216.
  17. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000;19:5720–5728.
  18. Klionsky DJ, Cuervo AM, Seglen PO: Methods for monitoring autophagy from yeast to human. Autophagy 2007;3:181–206.
  19. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P: Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000;275:992–998.
  20. Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, Ogier-Denis E: The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 2001;276:35243–35246.
  21. Noda T, Ohsumi Y: Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 1998;273:3963–3966.
  22. Kirkegaard K, Taylor MP, Jackson WT: Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol 2004;2:301–314.
  23. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441:885–889.
  24. Komatsu M, Waguri S, Chiba T, Murata S, Iwata JI, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880–884.
  25. Kim I, Rodriguez-Enriquez S, Lemasters JJ: Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 2007;462:245–253.
  26. 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.
  27. Bursch W: The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 2001;8:569–581.
  28. Gozuacik D, Kimchi A: Autophagy as a cell death and tumor suppressor mechanism. Oncogene 2004;23:2891–2906.
  29. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ: Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004;304:1500–1502.
  30. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B: Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 1998;72:8586–8596.
  31. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B: Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003;112:1809–1820.
  32. Yue Z, Jin S, Yang C, Levine AJ, Heintz N: Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003;100:15077–15082.
  33. Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B: Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999;59:59–65.
  34. Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, Le SS, Laessig TA, Heidenreich KA: The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J Neurosci 2004;24:4498–4509.
  35. Toth ML, Simon P, Kovacs AL, Vellai T: Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans. J Cell Sci 2007;120:1134–1141.
  36. Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N: A novel protein complex linking the δ2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron 2002;35:921–933.
  37. Orr HT: Lurcher, nPIST, and autophagy. Neuron 2002;35:813–814.
  38. Terman A, Brunk UT: Lipofuscin. Int J Biochem Cell Biol 2004;36:1400–1404.
  39. Terman A, Dalen H, Brunk UT: Ceroid/lipofuscin-loaded human fibroblasts show decreased survival time and diminished autophagocytosis during amino acid starvation. Exp Gerontol 1999;34:943–957.
  40. Donati A, Cavallini G, Paradiso C, Vittorini S, Pollera M, Gori Z, Bergamini E: Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. J Gerontol A Biol Sci Med Sci 2001;56:B288–B293.
  41. Cuervo AM, Dice JF: Age-related decline in chaperone-mediated autophagy. J Biol Chem 2000;275:31505–31513.
  42. Dice JF: Chaperone-mediated autophagy. Autophagy 2007;3:295–299.
  43. Ward WF: Protein degradation in the aging organism. Prog Mol Subcell Biol 2002;29:35–42.
  44. Terman A: The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology 1995;41(suppl 2):319–326.

    External Resources

  45. Hollenbeck PJ: Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol 1993;121:305–315.
  46. Yue Z: Regulation of neuronal autophagy in axon: implication of autophagy in axonal function and dysfunction/degeneration. Autophagy 2007;3:139–141.
  47. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM: Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005;64:113–122.
  48. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA: Macroautophagy – a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 2005;171:87–98.
  49. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y: Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 1997;12:25–31.
  50. Sikorska B, Liberski PP, Giraud P, Kopp N, Brown P: Autophagy is a part of ultrastructural synaptic pathology in Creutzfeldt-Jakob disease: a brain biopsy study. Int J Biochem Cell Biol 2004;36:2563–2573.
  51. Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, Vonsattel JP, Aronin N, DiFiglia M: Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 1997;42:604–612.
  52. Kegel KB, Kim M, Sapp E, McIntyre C, Castano JG, Aronin N, DiFiglia M: Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 2000;20:7268–7278.
  53. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S, Fischbeck KH: Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 2003;12:749–757.
  54. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ, Rubinsztein DC: 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.
  55. 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.
  56. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP: HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007;447:859–863.
  57. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, Sulzer D: Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 2001;10:1243–1254.
  58. Skinner PJ, Vierra-Green CA, Clark HB, Zoghbi HY, Orr HT: Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic mice. Am J Pathol 2001;159:905–913.
  59. Ravikumar B, Duden R, Rubinsztein DC: Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002;11:1107–1117.
  60. Kabuta T, Suzuki Y, Wada K: Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J Biol Chem 2006;281:30524–30533.
  61. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305:1292–1295.
  62. Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, Kopito RR: Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci USA 2005;102:13135–13140.
  63. Yamamoto A, Cremona ML, Rothman JE: Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 2006;172:719–731.
  64. Kuma A, Matsui M, Mizushima N: LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization. Autophagy 2007;3:323–328.
  65. Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, Schulz-Schaeffer W, Watanabe T, Waguri S, Kametaka S, Shibata M, Yamamoto K, Kominami E, Peters C, von Figura K, Uchiyama Y: Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci 2000;20:6898–6906.
  66. Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, Gotow T, Peters C, von Figura K, Mizushima N, Saftig P, Uchiyama Y: Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 2005;167:1713–1728.
  67. Shacka JJ, Klocke BJ, Young C, Shibata M, Olney JW, Uchiyama Y, Saftig P, Roth KA: Cathepsin D deficiency induces persistent neurodegeneration in the absence of Bax-dependent apoptosis. J Neurosci 2007;27:2081–2090.
  68. Myllykangas L, Tyynela J, Page-McCaw A, Rubin GM, Haltia MJ, Feany MB: Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses. Neurobiol Dis 2005;19:194–199.
  69. Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC: Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006;15:1209–1216.
  70. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O’Kane CJ, Brown SD, Rubinsztein DC: Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 2005;37:771–776.
  71. Jia K, Hart AC, Levine B: Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. Autophagy 2007;3:21–25.
  72. Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, Webster JA, Lewis TA, O’Kane CJ, Schreiber SL, Rubinsztein DC: Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 2007;3:331–338.
  73. Kenyon C: The plasticity of aging: insights from long-lived mutants. Cell 2005;120:449–460.
  74. Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B: Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 2003;301:1387–1391.
  75. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A: Opposing activities protect against age-onset proteotoxicity. Science 2006;313:1604–1610.
  76. Florez-McClure ML, Hohsfield LA, Fonte G, Bealor MT, Link CD: Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C. elegans. Autophagy 2007, E-pub ahead of print.

 goto top of outline Author Contacts

J. Paul Taylor
Taylor Lab, 233 Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104 (USA)
Tel. +1 215 573 2270, Fax +1 215 573 1153, E-Mail jpt@mail.med.upenn.edu


 goto top of outline Article Information

Published online: December 5, 2007
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 0, Number of References : 76


 goto top of outline Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


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