Skip to main content

Advertisement

Log in

Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Neuronal survival is highly dependent on autophagy due to its post-mitotic nature, polarized morphology, and active protein trafficking. Autophagic dysfunction has been linked to several neuronal diseases. Our understanding is still incomplete but may highlight up-to-date findings on how autophagy is executed and regulated at the molecular level and its role in neurodegenerative diseases (including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS)), brain ischemia, and myelin diseases, hence providing attractive new avenues for the development of treatment strategies to combat neuronal diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rubinsztein DC, Codogno P, Levine B (2012) Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 11:709–730. doi:10.1038/nrd3802, Review

  2. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. doi:10.1016/j.cell.2011.10.026

    Article  CAS  PubMed  Google Scholar 

  3. Wirawan E, Vanden Berghe T, Lippens S et al (2012) Autophagy: for better or for worse. Cell Res 22:43–61. doi:10.1038/cr.2011.152

    Article  CAS  PubMed  Google Scholar 

  4. Mijaljica D, Prescott M, Devenish RJ (2011) V-ATPase engagement in autophagic processes. Autophagy 7(6):666–668

    Article  CAS  PubMed  Google Scholar 

  5. Sahu R, Kaushik S, Clement CC et al (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20(1):131–139. doi:10.1016/j.devcel.2010.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Uttenweiler A, Mayer A (2008) Microautophagy in the yeast Saccharomyces cerevisiae. Methods Mol Biol 445:245–259. doi:10.1007/978-1-59745-157-4-16

    Article  CAS  PubMed  Google Scholar 

  7. van der Vaart A, Mari M, Reggiori F (2008) A picky eater: exploring the mechanisms of selective autophagy in human pathologies. Traffic 9(3):281–289

    Article  PubMed  CAS  Google Scholar 

  8. Kraft C, Reggiori F, Peter M (2009) Selective types of autophagy in yeast. Biochim Biophys Acta 1793(9):1404–12. doi:10.1038/cdd.2012.73, Review

  9. Beau I, Esclatine A, Codogno P (2008) Lost to translation: when autophagy targets mature ribosomes. Trends Cell Biol 18(7):311–314. doi:10.1016/j.tcb.2008.05.001, Review

  10. Li W, Yang Q, Mao Z (2011) Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci 68(5):749–763. doi:10.1007/s00018-010-0565-6

    Article  CAS  PubMed  Google Scholar 

  11. Dice JF (1990) Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 15(8):305–309

    Article  CAS  PubMed  Google Scholar 

  12. Mizushima N (2005) The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 12(Suppl 2):1535–41

    Article  CAS  PubMed  Google Scholar 

  13. Klionsky DJ, Cuervo AM, Dunn WA Jr et al (2007) How shall I eat thee? Autophagy 3(5):413–416

    Article  PubMed  Google Scholar 

  14. Kirkin V, McEwan DG, Novak I et al (2009) A role for ubiquitin in selective autophagy. Mol Cell 34(3):259–69. doi:10.1016/j.molcel.2009.04.026, Review

  15. Massey AC, Kaushik S, Sovak G et al (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 103(15):5805–5810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kaushik S, Massey AC, Mizushima N et al (2008) Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol Biol Cell 19(5):2179–2192. doi:10.1091/mbc.E07-11-1155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ciechanover A, Heller H, Elias S et al (1980) ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc Natl Acad Sci U S A 77(3):1365–1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nandi D, Tahiliani P, Kumar A (2006) The ubiquitin-proteasome system. J Biosci 31(1):137–155, Review

    Article  CAS  PubMed  Google Scholar 

  19. Fuertes G, Villarroya A, Knecht E (2003) Role of proteasomes in the degradation of short-lived proteins in human fibroblasts under various growth conditions. Int J Biochem Cell Biol 35(5):651–64

    Article  CAS  PubMed  Google Scholar 

  20. Fuertes G, Martín De Llano JJ, Villarroya A et al (2003) Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. Biochem J 375(Pt 1):75–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Perlmutter DH (2002) The cellular response to aggregated proteins associated with human disease. J Clin Invest 110:1219–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555

    Article  CAS  PubMed  Google Scholar 

  24. Teckman JH, Burrows J, Hidvegi T et al (2001) The proteasome participates in degradation of mutant α1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J Biol Chem 276:44865–44872

    Article  CAS  PubMed  Google Scholar 

  25. Ravikumar B, Rubinsztein DC (2004) Can autophagy protect against neurodegeneration caused by aggregate-prone proteins? Neuroreport 15:2443–2445

    Article  PubMed  Google Scholar 

  26. Teckman JH, Perlmutter DH (2000) Retention of mutant α(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physio 279:G961–G974

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Kamimoto T, Shoji S, Hidvegi T et al (2006) Intracellular inclusions containing mutant α1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 281:4467–4476

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Kruse KB, Brodsky JL, McCracken AA (2006) Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human α-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell 17:203–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kruse KB, Dear A, Kaltenbrun ER et al (2006) Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 168:1299–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pandey UB, Batlevi Y, Baehrecke EH et al (2007) HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration. Autophagy 3(6):643–645

    Article  CAS  PubMed  Google Scholar 

  33. Bjørkøy G, Lamark T, Brech A et al (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171(4):603–614

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Simonsen A, Birkeland HC, Gillooly DJ et al (2004) Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci 117(Pt 18):4239–4251

    Article  CAS  PubMed  Google Scholar 

  35. Korolchuk VI, Mansilla A et al (2009) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 33(4):517–527. doi:10.1016/j.molcel.2009.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Korolchuk VI, Menzies FM, Rubinsztein DC (2010) Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584(7):1393–1398. doi:10.1016/j.febslet.2009.12.047

    Article  CAS  PubMed  Google Scholar 

  37. Ding WX, Ni HM, Gao W et al (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rubinsztein DC, Shpilka T, Elazar Z (2012) Mechanisms of autophagosome biogenesis. Curr Biol 22:R229–R234. doi:10.1016/j.cub.2011.11.034, Review

  39. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93. doi:10.1146/annurev-genet-102808-114910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Klionsky DJ, Cregg JM, Dunn WA Jr et al (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5(4):539–545

    Article  CAS  PubMed  Google Scholar 

  41. Thumm M, Egner R, Koch B et al (1994) Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349(2):275–280

    Article  CAS  PubMed  Google Scholar 

  42. Pyo JO, Nah J, Jung YK (2012) Molecules and their functions in autophagy. Exp Mol Med 44(2):73–80. doi:10.3858/emm.2012.44.2.029, Review

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Axe EL, Walker SA, Manifava M et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701. doi:10.1083/jcb.200803137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheong H, Nair U, Geng J (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19:668–681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kabeya Y, Kamada Y, Baba M et al (2005) Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Mol Biol Cell 16:2544–2553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kamada Y, Funakoshi T, Shintani T et al (2000) Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150:1507–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cheong H, Klionsky DJ (2008) Dual role of Atg1 in regulation of autophagy-specific PAS assembly in Saccharomyces cerevisiae. Autophagy 4:724–726

    Article  CAS  PubMed  Google Scholar 

  48. Kawamata T, Kamada Y, Kabeya Y (2008) Organization of the pre-autophagosomal structure responsible for autophagosome formation. Mol Biol Cell 19:2039–2050. doi:10.1091/mbc.E07-10-1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Suzuki K, Kubota Y, Sekito T, Ohsumi Y (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 12:209–218

    Article  CAS  PubMed  Google Scholar 

  50. Ganley IG, du Lam H, Wang J et al (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297–12305. doi:10.1074/jbc.M900573200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hosokawa N, Hara T, Kaizuka T et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991. doi:10.1091/mbc.E08-12-1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jung CH, Jun CB, Ro SH et al (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992–2003. doi:10.1091/mbc.E08-12-1249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nakahara Y, Suzuki-Migishima R, Yokoyama M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889

    Article  PubMed  CAS  Google Scholar 

  54. Mercer CA, Kaliappan A, Dennis PB (2009) A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5(7):973–979

    Article  Google Scholar 

  55. Hosokawa N, Sasaki T, Iemura S et al (2009) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5(7):973–979

    Article  CAS  PubMed  Google Scholar 

  56. Itakura E, Kishi C, Inoue K et al (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19:5360–5372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sun Q, Fan W, Chen K et al (2008) Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 105:19211–19216. doi:10.1073/pnas.0810452105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Decuypere JP, Parys JB, Bultynck G (2012) Regulation of the autophagic bcl-2/beclin 1 interaction. Cells 1(3):284–312. doi:10.3390/cells1030284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Burda P, Padilla SM, Sarkar S (2002) Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci 115:3889–390060

    Article  CAS  PubMed  Google Scholar 

  60. He C, Levine B (2010) The Beclin 1 interactome. Curr Opin Cell Biol 22:140–149. doi:10.1016/j.ceb.2010.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gordy C, He YW (2012) The crosstalk between autophagy and apoptosis: where does this lead? Protein Cell 3:17–27. doi:10.1007/s13238-011-1127-x

    Article  PubMed  PubMed Central  Google Scholar 

  62. Konishi A, Arakawa S, Yue Z et al (2012) Involvement of Beclin 1 in engulfment of apoptotic cells. J Biol Chem 287:13919–13929. doi:10.1074/jbc.M112.348375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Funderburk SF, Wang QJ, Yue Z (2010) The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond. Trends Cell Biol 20:355–362. doi:10.1016/j.tcb.2010.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liang C, Lee JS, Inn KS et al (2008) Beclin 1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10:776–787. doi:10.1038/ncb1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Matsunaga K, Saitoh T, Tabata K et al (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396. doi:10.1038/ncb1846

    Article  CAS  PubMed  Google Scholar 

  66. Fimia GM, Stoykova A, Romagnoli A et al (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–1125

    CAS  PubMed  Google Scholar 

  67. Takahashi Y, Coppola D, Matsushita N et al (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9:1142–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yue Z, Horton A, Bravin M et al (2002) A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron 35:921–33

    Article  CAS  PubMed  Google Scholar 

  69. Vicencio JM, Ortiz C, Criollo A et al (2009) The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 16:1006–1017. doi:10.1038/cdd.2009.34

    Article  CAS  PubMed  Google Scholar 

  70. Ropolo A, Grasso D, Pardo R et al (2007) The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. J Biol Chem 282:37124–37133

    Article  CAS  PubMed  Google Scholar 

  71. Kang R, Livesey KM, Zeh HJ et al (2010) HMGB1: a novel Beclin 1-binding protein active in autophagy. Autophagy 6:1209–1211

    Article  CAS  PubMed  Google Scholar 

  72. Wei Y, Pattingre S, Sinha S et al (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678–88. doi:10.1016/j.molcel.2008.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pattingre S, Tassa A, Qu X et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  CAS  PubMed  Google Scholar 

  74. Zalckvar E, Berissi H, Mizrachy L (2009) DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 10(3):285–292. doi:10.1038/embor.2008.246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Noda T, Kim J, Huang WP et al (2000) Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways. J Cell Biol 148:465–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yamamoto H, Kakuta S, Watanabe TM et al (2012) Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol 198(2):219–33. doi:10.1083/jcb.201202061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mari MI, Griffith J, Rieter E (2010) An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol 190:1005–1022. doi:10.1083/jcb.200912089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Orsi AI, Razi M, Dooley HC, Robinson D (2012) Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23:1860–1873. doi:10.1091/mbc.E11-09-0746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kageyama S, Omori H, Saitoh T et al (2011) The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella. Mol Biol Cell 22(13):2290–2300. doi:10.1091/mbc.E10-11-0893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Itakura E, Mizushima N (2010) Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6:764–776. doi:10.4161/auto.6.6.12709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Young AR, Chan EY, Hu XW et al (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119(Pt 18):3888–900

    Article  CAS  PubMed  Google Scholar 

  82. Longatti AI, Lamb CA, Razi M (2012) TBC1D14 regulates autophagosome formation via Rab11-and ULK1-positive recycling endosomes. J Cell Biol 197(5):659–675. doi:10.1083/jcb.201111079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Reggiori F, Shintani T, Nair U et al (2005) Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts. Autophagy 1:101–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hailey DW, Rambold AS, Satpute-Krishnan P et al (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141(4):656–667. doi:10.1016/j.cell.2010.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Moreau K, Ravikumar B, Renna M et al (2011) Autophagosome precursor maturation requires homotypic fusion. Cell 146(2):303–317. doi:10.1016/j.cell.2011.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Esclatine A, Chaumorcel M, Codogno P (2009) Macroautophagy signaling and regulation. Curr Top Microbiol Immunol 335:33–70. doi:10.1007/978-3-642-00302-82, Review

  87. Ravikumar B, Imarisio S, Sarkar S et al (2008) Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 121:1649–1660. doi:10.1242/jcs.025726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ohsumi Y, Mizushima N (2004) Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol 15:231–236

    Article  CAS  PubMed  Google Scholar 

  89. Hanada T, Noda NN, Satomi Y et al (2007) The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282:37298–37302

    Article  CAS  PubMed  Google Scholar 

  90. Fujita N, Itoh T, Omori H et al (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19:2092–2100. doi:10.1091/mbc. E07-12-1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee KM, Hwang SK, Lee JA (2013) Neuronal autophagy and neurodevelopmental disorders. Neurobiol 22(3):133–142. doi:10.5607/en.2013.22.3.133

    Article  Google Scholar 

  92. Burman C, Ktistakis NT (2010) Autophagosome formation in mammalian cells. Semin Immunopathol 32:397–413. doi:10.1007/s00281-010-0222-z

    Article  CAS  PubMed  Google Scholar 

  93. Nemoto T, Tanida I, Tanida-Miyake E et al (2003) The mouse APG10 homologue, an E2-like enzyme for Apg12p conjugation, facilitates MAP-LC3 modification. J Biol Chem 278:39517–39526

    Article  CAS  PubMed  Google Scholar 

  94. Tanida I, Tanida-Miyake E, Komatsu M et al (2002) Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, facilitates the conjugation of hApg12p to hApg5p. J Biol Chem 277:13739–13744

    Article  CAS  PubMed  Google Scholar 

  95. Nishida Y, Arakawa S, Fujitani K et al (2009) Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461:654–658. doi:10.1038/nature08455

    Article  CAS  PubMed  Google Scholar 

  96. Zhang J, Randall MS, Loyd MR et al (2009) Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation. Blood 114(1):157–64. doi:10.1182/blood-2008-04-151639

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kundu M, Lindsten T, Yang CY et al (2008) Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112(4):1493–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ Suppl 2:1509–1518

    Article  CAS  Google Scholar 

  99. Eskelinen EL (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1:1–10

    Article  CAS  PubMed  Google Scholar 

  100. Rubinsztein DC, Cuervo AM, Ravikumar B et al (2009) In search of an “autophagomometer”. Autophagy 5:585–589

    Article  CAS  PubMed  Google Scholar 

  101. Jaeger PA, Wyss-Coray T (2010) Beclin 1 complex in autophagy and Alzheimer disease. Arch Neurol 67(10):1181–1184. doi:10.1001/archneurol.2010.258

    Article  PubMed  Google Scholar 

  102. Lee JA, Gao FB (2012) Neuronal functions of ESCRTs. Exp Neurobiol 21:9–15. doi:10.5607/en.2012.21.1.9

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lee JA, Beigneux A, Ahmad ST (2007) ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr Biol 17:1561–1567

    Article  CAS  PubMed  Google Scholar 

  104. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Sci Signal 2(67):pe24. doi:10.1126/scisignal.267pe24

    Article  PubMed  Google Scholar 

  105. Høyer-Hansen MI, Jäättelä M (2007) AMP-activated protein kinase: a universal regulator of autophagy. Autophagy 3:381–338

    Article  PubMed  Google Scholar 

  106. Zheng MI, Wang YH, Wu XN (2011) Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat Cell Biol 13:263–272. doi:10.1038/ncb2168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484, Review

    Article  CAS  PubMed  Google Scholar 

  108. Sancak YI, Bar-Peled L, Zoncu R (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303. doi:10.1016/j.cell.2010.02.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gwinn DMI, Shackelford DB, Egan DF (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226. doi:10.1016/j.molcel.2008.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Levine B, Abrams J (2008) p53: the Janus of autophagy? Nat Cell Biol 10:637–639. doi:10.1038/ncb0608-637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tasdemir E, Chiara Maiuri M, Morselli E et al (2008) A dual role of p53 in the control of autophagy. Autophagy 4:810–814

    Article  CAS  PubMed  Google Scholar 

  112. Feng Z, Zhang H, Levine AJ et al (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204–8209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Crighton D, Wilkinson S, O’Prey J et al (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121–124

    Article  CAS  PubMed  Google Scholar 

  114. Morselli EI, Maiuri MC, Markaki M (2010) The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6:186–188

    Article  PubMed  Google Scholar 

  115. Tasdemir E, Maiuri MC, Galluzzi L et al (2008) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10:676–687. doi:10.1038/ncb1730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Armour SM, Baur JA, Hsieh SN et al (2009) Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging (Albany NY) 1:515–528

    Article  CAS  Google Scholar 

  117. Yorimitsu T, Zaman S, Broach JR et al (2007) Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18:4180–4189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Abeliovich H, Dunn WA Jr, Kim J et al (2000) Dissection of autophagosome biogenesis into distinct nucleation and expansion steps. J Cell Biol 151:1025–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lawrence BP, Brown WJ (1993) Inhibition of protein synthesis separates autophagic sequestration from the delivery of lysosomal enzymes. J Cell Sci 105(Pt 2):473–480

    CAS  PubMed  Google Scholar 

  120. Chang YY, Juhasz G, Goraksha-Hicks P et al (2009) Nutrient-dependent regulation of autophagy through the target of rapamycin pathway. Biochem Soc Trans 37:232–236. doi:10.1042/BST0370232

    Article  CAS  PubMed  Google Scholar 

  121. Koren I, Reem E, Kimchi A (2010) DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 20:1093–1098. doi:10.1016/j.cub.2010.04.041

    Article  CAS  PubMed  Google Scholar 

  122. Thoreen CC, Kang SA, Chang JW et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032. doi:10.1074/jbc.M900301200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mammucari C, Milan G, Romanello V et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471

    Article  CAS  PubMed  Google Scholar 

  124. Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  CAS  PubMed  Google Scholar 

  125. Yu L, McPhee CK, Zheng L et al (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–946. doi:10.1038/nature09076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yu L, Alva A, Su H et al (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500–1502

    Article  CAS  PubMed  Google Scholar 

  127. Yu L, Lenardo MJ, Baehrecke EH (2004) Autophagy and caspases: a new cell death program. Cell Cycle 3:1124–1126, Review

    CAS  PubMed  Google Scholar 

  128. Yu L, Strandberg L, Lenardo MJ (2008) The selectivity of autophagy and its role in cell death and survival. Autophagy 4(5):567–573

    Article  PubMed  Google Scholar 

  129. Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361(6410):315–325, Review

    Article  CAS  PubMed  Google Scholar 

  130. Cherra SJ III, Kulich SM, Uechi G et al (2010) Regulation of the autophagy protein LC3 by phosphorylation. J Cell Biol 190:533–539. doi:10.1083/jcb.201002108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mavrakis M, Lippincott-Schwartz J, Stratakis CA et al (2006) Depletion of type IA regulatory subunit (RI) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Hum Mol Genet 15:2962–2971

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  133. Scherz-Shouval R, Shvets E, Fass E et al (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tooze SA, Schiavo G (2008) Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr Opin Neurobiol 18:504–515. doi:10.1016/j.conb.2008.09.015

    Article  CAS  PubMed  Google Scholar 

  136. Lee JA (2009) Autophagy in neurodegeneration: two sides of the same coin. BMB Rep 42(6):324–330

    Article  CAS  PubMed  Google Scholar 

  137. Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884

    Article  CAS  PubMed  Google Scholar 

  138. Boland B, Kumar A, Lee S et al (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 28(27):6926–6937. doi:10.1523/JNEUROSCI.0800-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Komatsu M, Wang QJ, Holstein GR et al (2007) Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci U S A 104:14489–14494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yue Z, Friedman L, Komatsu M et al (2009) The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim Biophys Acta 1793:1496–1507. doi:10.1016/j.bbamcr.2009.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yu WH, Cuervo AM, Kumar A et al (2005) Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171(1):87–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nixon RA, Wegiel J, Kumar A et al (2005) Extensive involvement of autophagy in Alzheimer disease: an immunoelectronmicroscopy study. J Neuropathol Exp Neurol 64:113–122

    Article  PubMed  Google Scholar 

  143. Mizushima N (2004) Methods for monitoring autophagy. Int J Biochem Cell Biol 36(12):2491–2502 Review.

  144. Dixon JS (1967) ‘Phagocytic’ lysosomes in chromatolytic neurones. Nature 215(5101):657–658

    Article  CAS  PubMed  Google Scholar 

  145. Matthews MR, Raisman G (1972) A light and electron microscopic study of the cellular response to axonal injury in the superior cervical ganglion of the rat. Proc R Soc Lond B Biol Sci 181(62):43–79

    Article  CAS  PubMed  Google Scholar 

  146. Broadwell RD, Cataldo AM (1984) The neuronal endoplasmic reticulum: its cytochemistry and contribution to the endomembrane system. II. Axons and terminals. J Comp Neurol 230(2):231–248

    Article  CAS  PubMed  Google Scholar 

  147. Hollenbeck PJ (1993) Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol 121(2):305–315

    Article  CAS  PubMed  Google Scholar 

  148. Maday S, Wallace KE, Holzbaur EL (2012) Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol 196(4):407–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Katsumata K, Nishiyama J, Inoue T et al (2010) Dynein- and activity-dependent retrograde transport of autophagosomes in neuronal axons. Autophagy 6(3):378–385. doi:10.1083/jcb.201106120

    Article  CAS  PubMed  Google Scholar 

  150. Rubinsztein DC, DiFiglia M, Heintz N, et al. (2005) Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1(1):11–22 Review

  151. Cheng HC, Kim SR, Oo TF et al (2011) Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J Neurosci 31(6):2125–2135. doi:10.1523/JNEUROSCI.5519-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rodriguez-Muela N, Germain F, Marino G et al (2012) Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. Cell Death Differ 19(1):162–169. doi:10.1038/cdd.2011.88

    Article  CAS  PubMed  Google Scholar 

  153. Wang QJ, Ding Y, Kohtz DS et al (2006) Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 26(31):8057–8068

    Article  CAS  PubMed  Google Scholar 

  154. Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889

    Article  CAS  PubMed  Google Scholar 

  155. Du L, Hickey RW, Bayir H et al (2009) Starving neurons show sex difference in autophagy. J Biol Chem 284(4):2383–2396. doi:10.1074/jbc.M804396200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Rose C, Menzies FM, Renna M et al (2010) Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 19:2144–2153. doi:10.1093/hmg/ddq093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Crews L, Spencer B, Desplats P et al (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE 5:e9313. doi:10.1371/journal.pone.0009313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Young JE, Martinez RA, La Spada AR (2009) Nutrient deprivation induces neuronal autophagy and implicates reduced insulin signaling in neuroprotective autophagy activation. J Biol Chem 284:2363–2373. doi:10.1074/jbc.M806088200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Yamamoto A, Cremona ML, Rothman JE (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172:719–731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sarkar S, Ravikumar B, Floto RA et al (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine expanded huntingtin and related proteinopathies. Cell Death Differ 16:46–56. doi:10.1038/cdd.2008.110

    Article  CAS  PubMed  Google Scholar 

  161. Tsvetkov AS, Miller J, Arrasate M et al (2010) A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A 107:16982–16987. doi:10.1073/pnas.1004498107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhang L, Yu J, Pan H et al (2007) Small molecule regulators of autophagy identified by an image-based highthroughput screen. Proc Natl Acad Sci U S A 104:19023–19028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lipinski MM, Hoffman G, Ng A et al (2010) A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Dev Cell 18:1041–1052. doi:10.1016/j.devcel.2010.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bains M, Zaegel V, Mize-Berge J et al (2011) IGF-I stimulates Rab7-RILP interaction during neuronal autophagy. Neurosci Lett 488:112–117. doi:10.1016/j.neulet.2010.09.018

    Article  CAS  PubMed  Google Scholar 

  165. Wong AS, Lee RH, Cheung AY et al (2011) Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson’s disease. Nat Cell Biol 13:568–579. doi:10.1038/ncb2217

    Article  CAS  PubMed  Google Scholar 

  166. Xu P, Das M, Reilly J et al (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25:310–322. doi:10.1101/gad.1984311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Cherra SJ, Chu CT (2008) Autophagy in neuroprotection and neurodegeneration: a question of balance. Future Neurol 3:309–323

    PubMed  PubMed Central  Google Scholar 

  168. Carra S, Brunsting JF, Lambert H et al (2009) HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2{alpha} phosphorylation. J Biol Chem 284(9):5523–32

    Article  CAS  PubMed  Google Scholar 

  169. Eskelinen EL (2006) Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Asp Med 27:495–502

    Article  CAS  Google Scholar 

  170. Nishino I (2006) Autophagic vacuolar myopathy. Semin Pediatr Neurol 13:90–95, Review

    Article  PubMed  Google Scholar 

  171. Carloni S, Buonocore G, Balduini W (2008) Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis Dec 32(3):329–39. doi:10.1016/j.nbd.2008.07.022

    Article  CAS  Google Scholar 

  172. Yitzhaki S, Huang C, Liu W et al (2009) Autophagy is required for preconditioning by the adenosine A1 receptor-selective agonist CCPA. Basic Res Cardiol 104:157–67. doi:10.1007/s00395-009-0006-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ghavami S, Shojaei S, Yeganeh B et al (2014) Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 112:24–49

    Article  CAS  PubMed  Google Scholar 

  174. Koike M, Shibata M, Tadakoshi M et al (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 172:454–469. doi:10.2353/ajpath.2008.070876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lee JA, Gao FB (2009) Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J Neurosci 29:8506–8511. doi:10.1523/JNEUROSCI.0924-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Lee S, Sato Y, Nixon RA (2011) Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J Neurosci 31:7817–7830. doi:10.1523/JNEUROSCI.6412-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  178. Ju JS, Fuentealba RA, Miller SE et al (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–878. doi:10.1083/jcb.200908115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Lee JA, Gao FB (2008) ESCRT, autophagy, and frontotemporal dementia. BMB Rep 41:827–832, Review

    Article  CAS  PubMed  Google Scholar 

  180. Pasquali L, Ruffoli R, Fulceri F et al (2010) The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis. CNS Neurol Disord Drug Targets 9:268–278

    Article  CAS  PubMed  Google Scholar 

  181. Mizushima N, Levine B, Cuervo AM et al (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075. doi:10.1038/nature06639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hung SY, Huang WP, Liou HC et al (2009) Autophagy protects neuron from Abeta-induced cytotoxicity. Autophagy 5:502–510

    Article  CAS  PubMed  Google Scholar 

  183. Wang H, Ma J, Tan Y et al (2010) Amyloid-beta1-42 induces reactive oxygen species-mediated autophagic cell death in U87 and SH-SY5Y cells. J Alzheimers Dis 21:597–610. doi:10.3233/JAD-2010-091207

    CAS  PubMed  Google Scholar 

  184. Boland B, Smith DA, Mooney D et al (2010) Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J Biol Chem 285:37415–37426. doi:10.1074/jbc.M110.186411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204. doi:10.1146/annurev-neuro-061010-113613, Review

  186. Rajendran L, Annaert W (2012) Membrane trafficking pathways in Alzheimer’s disease. Traffic 13:759–770. doi:10.1111/j.1600-0854.2012.01332.x

    Article  CAS  PubMed  Google Scholar 

  187. Pickford F, Masliah E, Britschgi M et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199. doi:10.1172/JCI33585

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Jaeger PA, Pickford F, Sun CH et al (2010) Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS ONE 5:e11102. doi:10.1371/journal.pone.0011102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Spencer B, Potkar R, Trejo M et al (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588. doi:10.1523/JNEUROSCI.4390-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Lee JH, Yu WH, Kumar A et al (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer related PS1 mutations. Cell 141:1146–1158. doi:10.1016/j.cell.2010.05.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  192. Wang Y, Martinez-Vicente M, Kruger U et al (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Caccamo A, Majumder S, Richardson A et al (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285:13107–13120. doi:10.1093/hmg/ddp367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Rodriguez-Navarro JA, Rodriguez L, Casarejos MJ et al (2010) Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis 39:423–438. doi:10.1016/j.nbd.2010.05.014

    Article  CAS  PubMed  Google Scholar 

  195. Majumder S, Richardson A, Strong R et al (2011) Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 6:e25416. doi:10.1371/journal.pone.0025416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Schaeffer V, Lavenir I, Ozcelik S et al (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 135:2169–2177. doi:10.1093/brain/aws143

    Article  PubMed  PubMed Central  Google Scholar 

  197. Lee JY, Koga H, Kawaguchi Y et al (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980. doi:10.1038/emboj.2009.405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384, Review

    Article  CAS  PubMed  Google Scholar 

  199. Finkbeiner S (2011) Huntington’s disease. Cold Spring Harb Perspect Biol 3(6):a007476. doi:10.1101/cshperspect.a007476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Tellez-Nagel I, Johnson AB, Terry RD (1974) Studies on brain biopsies of patients with Huntington’s chorea. J Neuropathol Exp Neurol 33:308–332

    Article  CAS  PubMed  Google Scholar 

  201. Wang T, Lao U, Edgar BA (2009) TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol 186:703–711. doi:10.1083/jcb.200904090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Sarkar S, Rubinsztein DC (2008) Huntington’s disease: degradation of mutant huntingtin by autophagy. Febs J 275:4263–4270

    Article  CAS  PubMed  Google Scholar 

  203. Martinez-Vicente M, Talloczy Z, Wong E et al (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 13:567–576. doi:10.1038/nn.2528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Li X, Wang CE, Huang S et al (2010) Inhibiting the ubiquitin-proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments. Hum Mol Genet 19:2445–2455. doi:10.1093/hmg/ddq127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Zheng S, Clabough EB, Sarkar S et al (2010) Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet 6:e1000838. doi:10.1371/journal.pgen.1000838

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Atwal RS, Truant R (2008) A stress sensitive ER membrane association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy. Autophagy 4:91–93

    Article  PubMed  Google Scholar 

  207. Berger Z, Ravikumar B, Menzies FM et al (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15:433–442. doi:10.1093/hmg/ddi458

    Article  CAS  PubMed  Google Scholar 

  208. Williams A, Sarkar S, Cuddon P et al (2008) Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol 4:295–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Tsvetkov AS, Miller J, Arrasate M et al (2010) A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A 107:16982–16987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Rose C, Menzies FM, Renna M et al (2010) Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 19:2144–2153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Chakrabarti L, Eng J, Ivanov N et al (2009) Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol Brain 2:2410

    Article  CAS  Google Scholar 

  212. Anglade P, Vyas S, Javoy-Agid F et al (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  215. Nuytemans K, Theuns J, Cruts M et al (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31:763–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Isidoro C, Biagioni F, Giorgi FS et al (2009) The role of autophagy on the survival of dopamine neurons. Curr Top Med Chem 9:869–879

    CAS  PubMed  Google Scholar 

  217. Winslow AR, Chen CW, Corrochano S et al (2011) Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037. doi:10.1083/jcb.201003122

    Article  CAS  Google Scholar 

  218. Xilouri M, Vogiatzi T, Vekrellis K et al (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE 4:e5515. doi:10.1371/journal.pone.0005515

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Narendra D, Tanaka A, Suen DF et al (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803. doi:10.1083/jcb.200809125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Vives-Bauza C, Zhou C, Huang Y et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107:378–383. doi:10.1073/pnas.0911187107

    Article  CAS  PubMed  Google Scholar 

  221. Michiorri S, Gelmetti V, Giarda E et al (2010) The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ 17:962–974. doi:10.1038/cdd.2009.200

    Article  CAS  PubMed  Google Scholar 

  222. Khandelwal PJ, Herman AM, Hoe HS et al (2011) Parkin mediates Beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20:2091–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Stefanis L, Larsen KE, Rideout HJ et al (2001) 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 21:9549–9560

    CAS  PubMed  Google Scholar 

  224. Choubey V, Safiulina D, Vaarmann A et al (2011) Mutant A53T (alpha)-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem 286:10814–10824. doi:10.1074/jbc.M110.132514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Zhu JH, Horbinski C, Guo F et al (2007) Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol 170:75–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Choi KC, Kim SH, Ha JY et al (2010) A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. J Neurochem 112:366–376. doi:10.1111/j.1471-4159.2009.06463.x

    Article  CAS  PubMed  Google Scholar 

  227. Tofaris GK (2012) Lysosome-dependent pathways as a unifying theme in Parkinson’s disease. Mov Disord 27:1364–1369. doi:10.1002/mds.25136

    Article  CAS  PubMed  Google Scholar 

  228. Janda E, Isidoro C, Carresi C et al (2012) Defective autophagy in Parkinson’s disease: role of oxidative stress. Mol Neurobiol 46:639–661. doi:10.1007/s12035-012-8318-1

    Article  CAS  PubMed  Google Scholar 

  229. Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7(11):603–615. doi:10.1038/nrneurol.2011.150

    Article  CAS  PubMed  Google Scholar 

  230. Hardiman O, van den Berg LH, Kiernan MC (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol 7(11):639–649

    Article  CAS  PubMed  Google Scholar 

  231. Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70(5):349–359. doi:10.1038/nrneurol.2011.153

    Article  PubMed  Google Scholar 

  232. Li L, Zhang X, Le W (2008) Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4:290–293

    Article  CAS  PubMed  Google Scholar 

  233. Morimoto N, Nagai M, Ohta Y et al (2007) Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res 1167:112–117

    Article  CAS  PubMed  Google Scholar 

  234. Crippa V et al (2010) The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 19:3440–3456

    Article  CAS  PubMed  Google Scholar 

  235. Hetz C et al (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Filimonenko M, Stuffers S, Raiborg C et al (2007) Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 179:485–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–64. doi:10.1016/j.neuron.2010.11.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Uchiyama Y (2001) Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol 64:233–246

    Article  CAS  PubMed  Google Scholar 

  239. Uchiyama Y, Koike M, Shibata M (2008) Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy 4:404–408

    Article  CAS  PubMed  Google Scholar 

  240. Wen YD, Sheng R, Zhang LS et al (2008) Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 4:762–769

    Article  CAS  PubMed  Google Scholar 

  241. Wang JY, Xia Q, Chu KT et al (2011) Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. J Neuropathol Exp Neurol 70:314–322. doi:10.1097/NEN.0b013e31821352bd

    Article  CAS  PubMed  Google Scholar 

  242. Tanabe F, Yone K, Kawabata N et al (2011) Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: functional analysis of p62 and autophagy in hypoxic neuronal cells. Autophagy 7:1462–1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Wang P, Guan YF, Du H et al (2012) Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 8:77–87. doi:10.4161/auto.8.1.18274

    Article  CAS  PubMed  Google Scholar 

  244. Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269:1996–2002

    Article  CAS  PubMed  Google Scholar 

  245. Liu C, Gao Y, Barrett J et al (2010) Autophagy and protein aggregation after brain ischemia. J Neurochem 115(1):68–78. doi:10.1111/j.1471-4159.2010.06905.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Qin AP, Liu CF, Qin YY et al (2010) Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy 6(6):738–753

    Article  CAS  PubMed  Google Scholar 

  247. Cui D, Wang L, Qi A et al (2012) Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. PLoS ONE 7(4):e35324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Gao L, Jiang T, Guo J et al (2012) Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. PLoS One 7(9):e46092. doi:10.1371/journal.pone.0046092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Wang JY, Xia Q, Chu KT et al (2011) Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. J Neuropathol Exp Neurol 70:314–322

    Article  CAS  PubMed  Google Scholar 

  250. Sheng R, Zhang LS, Han R et al (2010) Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 6:482–494

    Article  CAS  PubMed  Google Scholar 

  251. Zhu C, Wang X, Xu F et al (2004) The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ 12:162–176

    Article  CAS  Google Scholar 

  252. Dirnagl U, Simon RP, Hallenbeck JM (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26:248–254

    Article  CAS  PubMed  Google Scholar 

  253. Rangaraju S, Notterpek L (2011) Autophagy aids membrane expansion by neuropathic Schwann cells. Autophagy 7:238–239

    Article  PubMed  PubMed Central  Google Scholar 

  254. Madorsky I, Opalach K, Waber A et al (2009) Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease. Neurobiol Dis 34:146–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Smith CM, Mayer JA, Duncan ID (2013) Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant. J Neurosci 33nn:8088–8100. doi:10.1523/JNEUROSCI.0233-13.2013

    Article  CAS  Google Scholar 

  256. van Kollenburg B, van Dijk J et al (2006) Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol 65:707–715

    Article  PubMed  Google Scholar 

  257. Getts MT, Getts DR, Kohm AP et al (2008) Endoplasmic reticulum stress response as a potential therapeutic target in multiple sclerosis. Therapy 5:631–640

    Article  PubMed  PubMed Central  Google Scholar 

  258. Dhaunchak AS, Nave KA (2007) A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease. Proc Natl Acad Sci U S A 104:17813–17818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Binbin Yang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Z., Yang, B., Mo, X. et al. Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases. Mol Neurobiol 52, 1190–1209 (2015). https://doi.org/10.1007/s12035-014-8921-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8921-4

Keywords

Navigation