Skip to main content

Advertisement

SpringerLink
Log in

Autophagic activity in neuronal cell death

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

As post-mitotic cells with great energy demands, neurons depend upon the homeostatic and waste-recycling functions provided by autophagy. In addition, autophagy also promotes survival during periods of harsh stress and targets aggregate-prone proteins associated with neurodegeneration for degradation. Despite this, autophagy has also been controversially described as a mechanism of programmed cell death. Instances of autophagic cell death are typically associated with elevated numbers of cytoplasmic autophagosomes, which have been assumed to lead to excessive degradation of cellular components. Due to the high activity and reliance on autophagy in neurons, these cells may be particularly susceptible to autophagic death. In this review, we summarize and assess current evidence in support of autophagic cell death in neurons, as well as how the dysregulation of autophagy commonly seen in neurodegeneration can contribute to neuron loss. From here, we discuss potential treatment strategies relevant to such cell-death pathways.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Feng Y, He D, Yao Z, Klionsky DJ. The machinery of macroautophagy. Cell Res 2014, 24: 24–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Shibutani ST, Yoshimori T. A current perspective of autophagosome biogenesis. Cell Res 2014, 24: 58–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010, 12: 814–822.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Rabinowitz JD, White E. Autophagy and metabolism. Science 2010, 330: 1344–1348.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Russell RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Res 2014, 24: 42–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012, 11: 709–730.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Button RW, Lin F, Ercolano E, Vincent JH, Hu B, Hanemann CO, et al. Artesunate induces necrotic cell death in schwannoma cells. Cell Death Dis 2014, 5: e1466.

    CAS  PubMed  Google Scholar 

  8. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011, 469: 323–335.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009, 137: 1062–1075.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini PF, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol 2015, 17: 20–30.

    CAS  PubMed  Google Scholar 

  11. Ding WX, Ni HM, Gao W, Chen X, Kang JH, Stolz DB, et al. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther 2009, 8: 2036–2045.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev 2011, 25: 1999–2010.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. 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.

    CAS  PubMed  Google Scholar 

  14. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 2009, 16: 46–56.

    CAS  PubMed  Google Scholar 

  15. Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L. Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy. Neurobiol Aging 2014, 35: 941–957.

    PubMed  Google Scholar 

  16. Ohsumi Y. Historical landmarks of autophagy research. Cell Res 2014, 24: 9–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Schweichel JU, Merker HJ. The morphology of various types of cell death in prenatal tissues. Teratology 1973, 7: 253–266.

    CAS  PubMed  Google Scholar 

  18. Kourtis N, Tavernarakis N. Autophagy and cell death in model organisms. Cell Death Differ 2009, 16: 21–30.

    CAS  PubMed  Google Scholar 

  19. Clarke PG, Puyal J. Autophagic cell death exists. Autophagy 2012, 8: 867–869.

    PubMed Central  PubMed  Google Scholar 

  20. Shi R, Weng J, Zhao L, Li XM, Gao TM, Kong J. Excessive autophagy contributes to neuron death in cerebral ischemia. CNS Neurosci Ther 2012, 18: 250–260.

    CAS  PubMed  Google Scholar 

  21. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 2004, 6: 1221–1228.

    CAS  PubMed  Google Scholar 

  22. Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008, 9: 1004–1010.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Shen S, Kepp O, Kroemer G. The end of autophagic cell death? Autophagy 2012, 8: 1–3.

    PubMed  Google Scholar 

  24. Shen HM, Codogno P. Autophagic cell death: Loch Ness monster or endangered species? Autophagy 2011, 7: 457–465.

    CAS  PubMed  Google Scholar 

  25. Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, et al. PGC-1alpha rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 2012, 4: 142ra197.

    Google Scholar 

  26. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 2008, 28: 6926–6937.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Nikoletopoulou V, Papandreou M, Tavernarakis N. Autophagy in the physiology and pathology of the central nervous system. Cell Death Differ 2014.

    Google Scholar 

  28. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 1993, 333: 169–174.

    CAS  PubMed  Google Scholar 

  29. Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, et al. Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 1994, 349: 275–280.

    CAS  PubMed  Google Scholar 

  30. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010, 12: 823–830.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Yang Z, Klionsky DJ. An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 2009, 335: 1–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 2008, 182: 685–701.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009, 11: 1433–1437.

    CAS  PubMed  Google Scholar 

  34. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of preautophagosomal structures. Nat Cell Biol 2010, 12: 747–757.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Ravikumar B, Moreau K, Rubinsztein DC. Plasma membrane helps autophagosomes grow. Autophagy 2010, 6: 1184–1186.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Puri C, Renna M, Bento CF, Moreau K, Rubinsztein DC. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 2013, 154: 1285–1299.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010, 141: 656–667.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. van der Vaart A, Griffith J, Reggiori F. Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol Biol Cell 2010, 21: 2270–2284.

    PubMed Central  PubMed  Google Scholar 

  39. Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 2010, 22: 132–139.

    CAS  PubMed  Google Scholar 

  40. Vicinanza M, Korolchuk VI, Ashkenazi A, Puri C, Menzies FM, Clarke JH, et al. PI(5)P regulates autophagosome biogenesis. Mol Cell 2015, 57: 219–234.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Klionsky DJ, Schulman BA. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol 2014, 21: 336–345.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, et al. The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. Embo j 2009, 28: 1341–1350.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 2008, 19: 2092–2100.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Shen HM, Mizushima N. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem Sci 2014, 39: 61–71.

    CAS  PubMed  Google Scholar 

  46. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441: 885–889.

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  48. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004, 15: 1101–1111.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Kanamori H, Takemura G, Maruyama R, Goto K, Tsujimoto A, Ogino A, et al. Functional significance and morphological characterization of starvation-induced autophagy in the adult heart. Am J Pathol 2009, 174: 1705–1714.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W. Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 2010, 6: 366–377.

    CAS  PubMed  Google Scholar 

  51. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011, 12: 9–14.

    CAS  PubMed  Google Scholar 

  52. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010, 189: 211–221.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Poillet-Perez L, Despouy G, Delage-Mourroux R, Boyer-Guittaut M. Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy. Redox Biol 2015, 4c: 184–192.

    Google Scholar 

  54. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 2005, 25: 1025–1040.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Luo S, Rubinsztein DC. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 2010, 17: 268–277.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Farkas T, Daugaard M, Jaattela M. Identification of small molecule inhibitors of phosphatidylinositol 3-kinase and autophagy. J Biol Chem 2011, 286: 38904–38912.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Luo S, Garcia-Arencibia M, Zhao R, Puri C, Toh PP, Sadiq O, et al. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol Cell 2012, 47: 359–370.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell 2014, 157: 1515–1526.

    PubMed Central  PubMed  Google Scholar 

  59. Menzies FM, Moreau K, Rubinsztein DC. Protein misfolding disorders and macroautophagy. Curr Opin Cell Biol 2011, 23: 190–197.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Cheung YT, Zhang NQ, Hung CH, Lai CS, Yu MS, So KF, et al. Temporal relationship of autophagy and apoptosis in neurons challenged by low molecular weight beta-amyloid peptide. J Cell Mol Med 2011, 15: 244–257.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, et al. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 2012, 32: 7585–7593.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Recasens A, Dehay B. Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 2014, 8: 159.

    PubMed Central  PubMed  Google Scholar 

  63. Martin DD, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci 2015, 38: 26–35.

    CAS  PubMed  Google Scholar 

  64. Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 2006, 281: 14474–14485.

    CAS  PubMed  Google Scholar 

  65. Michiorri S, Gelmetti V, Giarda E, Lombardi F, Romano F, Marongiu R, et al. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ 2010, 17: 962–974.

    CAS  PubMed  Google Scholar 

  66. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alphasynuclein models of Parkinson’s and Lewy body diseases. J Neurosci 2009, 29: 13578–13588.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc Natl Acad Sci U S A 2013, 110: E1817–1826.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, et al. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 2014, 17: 1180–1189.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 2010, 13: 567–576.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, et al. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A 2014, 111: 16889–16894.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 2010, 5: e9979.

    PubMed Central  PubMed  Google Scholar 

  72. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008, 118: 2190–2199.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010, 141: 1146–1158.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, et al. PICALM modulates autophagy activity and tau accumulation. Nat Commun 2014, 5: 4998.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, et al. alpha-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 2010, 190: 1023–1037.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Corrochano S, Renna M, Carter S, Chrobot N, Kent R, Stewart M, et al. alpha-Synuclein levels modulate Huntington’s disease in mice. Hum Mol Genet 2012, 21: 485–494.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 2014, 5: 3828.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012, 19: 107–120.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Berry DL, Baehrecke EH. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 2007, 131: 1137–1148.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, et al. Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Curr Biol 2009, 19: 1741–1746.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Chu CT. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006, 65: 423–432.

    PubMed Central  PubMed  Google Scholar 

  82. Grander D, Kharaziha P, Laane E, Pokrovskaja K, Panaretakis T. Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies. Autophagy 2009, 5: 1198–1200.

    CAS  PubMed  Google Scholar 

  83. Laane E, Tamm KP, Buentke E, Ito K, Kharaziha P, Oscarsson J, et al. Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. Cell Death Differ 2009, 16: 1018–1029.

    CAS  PubMed  Google Scholar 

  84. Elgendy M, Sheridan C, Brumatti G, Martin SJ. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell 2011, 42: 23–35.

    CAS  PubMed  Google Scholar 

  85. Sharma K, Le N, Alotaibi M, Gewirtz DA. Cytotoxic autophagy in cancer therapy. Int J Mol Sci 2014, 15: 10034–10051.

    PubMed Central  PubMed  Google Scholar 

  86. Liu Y, Shoji-Kawata S, Sumpter RM, Jr., Wei Y, Ginet V, Zhang L, et al. Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci U S A 2013, 110: 20364–20371.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Nezis IP, Shravage BV, Sagona AP, Lamark T, Bjorkoy G, Johansen T, et al. Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. J Cell Biol 2010, 190: 523–531.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Das G, Shravage BV, Baehrecke EH. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol 2012, 4.

  89. Chen W, Sun Y, Liu K, Sun X. Autophagy: a double-edged sword for neuronal survival after cerebral ischemia. Neural Regen Res 2014, 9: 1210–1216.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Xu F, Gu JH, Qin ZH. Neuronal autophagy in cerebral ischemia. Neurosci Bull 2012, 28: 658–666.

    CAS  PubMed  Google Scholar 

  91. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxiaischemia induced brain injury: evidence and speculations. Autophagy 2009, 5: 221–223.

    CAS  PubMed  Google Scholar 

  92. Wang P, Guan YF, Du H, Zhai QW, Su DF, Miao CY. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 2012, 8: 77–87.

    CAS  PubMed  Google Scholar 

  93. Ginet V, Spiehlmann A, Rummel C, Rudinskiy N, Grishchuk Y, Luthi-Carter R, et al. Involvement of autophagy in hypoxicexcitotoxic neuronal death. Autophagy 2014, 10: 846–860.

    CAS  PubMed  Google Scholar 

  94. Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 2008, 172: 454–469.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Xing S, Zhang Y, Li J, Zhang J, Li Y, Dang C, et al. Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction. Autophagy 2012, 8: 63–76.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  97. Puyal J, Vaslin A, Mottier V, Clarke PG. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol 2009, 66: 378–389.

    CAS  PubMed  Google Scholar 

  98. Munoz-Pinedo C, Martin SJ. Autosis: a new addition to the cell death tower of babel. Cell Death Dis 2014, 5: e1319.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 2015, 22: 367–376.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Kang C, Avery L. To be or not to be, the level of autophagy is the question: dual roles of autophagy in the survival response to starvation. Autophagy 2008, 4: 82–84.

    PubMed Central  PubMed  Google Scholar 

  101. Li IH, Ma KH, Weng SJ, Huang SS, Liang CM, Huang YS. Autophagy activation is involved in 3,4-methylenedioxymethamphetamine (‘ecstasy’)—induced neurotoxicity in cultured cortical neurons. PLoS One 2014, 9: e116565.

    PubMed Central  PubMed  Google Scholar 

  102. Liang JH, Jia JP. Dysfunctional autophagy in Alzheimer’s disease: pathogenic roles and therapeutic implications. Neurosci Bull 2014, 30: 308–316.

    CAS  PubMed  Google Scholar 

  103. Wu X, He L, Chen F, He X, Cai Y, Zhang G, et al. Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction. PLoS One 2014, 9: e112891.

    PubMed Central  PubMed  Google Scholar 

  104. Wu F, Xu HD, Guan JJ, Hou YS, Gu JH, Zhen XC, et al. Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease. Neuroscience 2015, 284: 900–911.

    CAS  PubMed  Google Scholar 

  105. Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, et al. Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 2010, 30: 12535–12544.

    CAS  PubMed  Google Scholar 

  106. Arduino DM, Esteves AR, Cortes L, Silva DF, Patel B, Grazina M, et al. Mitochondrial metabolism in Parkinson’s disease impairs quality control autophagy by hampering microtubule-dependent traffic. Hum Mol Genet 2012, 21: 4680–4702.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Lin TK, Chen SD, Chuang YC, Lin HY, Huang CR, Chuang JH, et al. Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci 2014, 15: 1625–1646.

    PubMed Central  PubMed  Google Scholar 

  108. Harris H, Rubinsztein DC. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 2012, 8: 108–117.

    CAS  Google Scholar 

  109. Hollerhage M, Goebel JN, de Andrade A, Hildebrandt T, Dolga A, Culmsee C, et al. Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity. Neurobiol Aging 2014, 35: 1700–1711.

    CAS  PubMed  Google Scholar 

  110. Rose C, Menzies FM, Renna M, Acevedo- Arozena A, Corrochano S, Sadiq O, et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 2010, 19: 2144–2153.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, 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.

    CAS  PubMed  Google Scholar 

  112. Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 2011, 6: e25416.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, et al. Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 2010, 5: e9313.

    PubMed Central  PubMed  Google Scholar 

  114. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 2010, 30: 1166–1175.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Buttner S, Broeskamp F, Sommer C, Markaki M, Habernig L, Alavian- Ghavanini A, et al. Spermidine protects against alpha-synuclein neurotoxicity. Cell Cycle 2014, 13: 3903–3908.

    PubMed  Google Scholar 

  116. Chu C, Zhang X, Ma W, Li L, Wang W, Shang L, et al. Induction of autophagy by a novel small molecule improves abeta pathology and ameliorates cognitive deficits. PLoS One 2013, 8: e65367.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, et al. Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J Neurosci 2013, 33: 13138–13149.

    CAS  PubMed  Google Scholar 

  118. Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 2011, 134: 258–277.

    PubMed Central  PubMed  Google Scholar 

  119. Stein VM, Crooks A, Ding W, Prociuk M, O’ Donnell P, Bryan C, et al. Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J Neuropathol Exp Neurol 2012, 71: 434–448.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Shen W, Henry AG, Paumier KL, Li L, Mou K, Dunlop J, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem 2014, 129: 884–894.

    CAS  PubMed  Google Scholar 

  121. Liao G, Yao Y, Liu J, Yu Z, Cheung S, Xie A, et al. Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 -/-mouse brain. Am J Pathol 2007, 171: 962–975.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Meske V, Priesnitz T, Albert F, Ohm TG. How to reduce the accumulation of autophagic vacuoles in NPC1-deficient neurons: A comparison of two pharmacological strategies. Neuropharmacology 2014, 89c: 282–289.

    Google Scholar 

  123. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. Science 2009, 325: 473–477.

    CAS  PubMed  Google Scholar 

  124. Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med 2014, 6: 1142–1160.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, PL6 8BU, UK

    Robert W. Button & Shouqing Luo

  2. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK

    David C. Rubinsztein

Authors
  1. Robert W. Button
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shouqing Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David C. Rubinsztein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shouqing Luo or David C. Rubinsztein.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Button, R.W., Luo, S. & Rubinsztein, D.C. Autophagic activity in neuronal cell death. Neurosci. Bull. 31, 382–394 (2015). https://doi.org/10.1007/s12264-015-1528-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-015-1528-y

Keywords

Search

Navigation