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Comparative Microarray Analysis Identifies Commonalities in Neuronal Injury: Evidence for Oxidative Stress, Dysfunction of Calcium Signalling, and Inhibition of Autophagy–Lysosomal Pathway

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Abstract

Mitochondrial dysfunction, ubiquitin-proteasomal system impairment and excitotoxicity occur during the injury and death of neurons in neurodegenerative conditions. The aim of this work was to elucidate the cellular mechanisms that are universally altered by these conditions. Through overlapping expression profiles of rotenone-, lactacystin- and N-methyl-d-aspartate-treated cortical neurons, we have identified three affected biological processes that are commonly affected; oxidative stress, dysfunction of calcium signalling and inhibition of the autophagic–lysosomal pathway. These data provides many opportunities for therapeutic intervention in neurodegenerative conditions, where mitochondrial dysfunction, proteasomal inhibition and excitotoxicity are evident.

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Abbreviations

AD:

Alzheimer’s disease

ALP:

Autophagy–lysosomal pathway

ALS:

Amyotrophic lateral sclerosis

CDK5:

Cyclin-dependent kinase5

CNS:

Central nervous system

c-Src:

c-terminal Src kinase

ER:

Endoplasmic reticulum

ERK1/2:

Extracellular signal-regulated kinase1/2

ETC:

Electron transport chain

Glu:

l-glutamate

GluR:

l-glutamate receptor

GSH:

Glutathione

GSK3β:

Glycogen synthase kinase-3β

HD:

Huntington’s disease

IMM:

Inner mitochondrial membrane

IP3R:

Inositol 1,4,5-trisphosphate receptor

JNK:

c-Jun N-terminal kinase

NMDA:

N-methyl-d-aspartate

NMDAR:

N-methyl-d-aspartate receptor

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

OMM:

Outer mitochondrial membrane

OS:

Oxidative stress

OXPHOS:

Oxidative phosphorylation system

PCD:

Programmed cell death

PD:

Parkinson’s disease

PFKFB3:

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3

PINK1:

PTEN-induced putative kinase 1

PKCδ:

Protein kinase C-δ

PSD-95:

Postsynaptic density-95

PTEN:

Phosphatase and tensin homolog

RONS:

Reactive oxygen and nitrogen species

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

SOD:

Cu2+/Zn2+ superoxide dismutase 1

sPLA2-IIA:

Group IIA secretory phospholipase A2

UPR:

Unfolded protein response

UPS:

Ubiquitin proteasome system

VGCC:

Voltage-gated Ca2+ channel

References

  1. Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P (2010) Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury. J Alzheimer Dis 20(Suppl 2):S453–S473

    Google Scholar 

  2. Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G, Hardwick JM (2004) Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 18:2785–2797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nagley P, Higgins GC, Atkin JD, Beart PM (2010) Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta 1802:167–185

    Article  CAS  PubMed  Google Scholar 

  4. Young KW, Bampton ET, Pinon L, Bano D, Nicotera P (2008) Mitochondrial Ca2+ signalling in hippocampal neurons. Cell Calcium 43:296–306

    Article  CAS  PubMed  Google Scholar 

  5. Lenaz G, Bovina C, D’Aurelio M, Fato R, Formiggini G, Genova ML, Giuliano G, Merlo Pich M, Paolucci U, Parenti Castelli G, Ventura B (2002) Role of mitochondria in oxidative stress and aging. Ann NY Acad Sci 959:199–213

    Article  CAS  PubMed  Google Scholar 

  6. Von Bernhardi R, Eugenin J (2012) Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal 16:974–1031

    Article  CAS  Google Scholar 

  7. Smeitink JA, van den Heuvel LW, DiMauro S (2001) The genetics and pathology of oxidative phosphorylation. Nature Rev Genet 2:342–352

    Article  CAS  PubMed  Google Scholar 

  8. Smeitink JA, van den Heuvel LW, Koopman WJ, Nijtmans LG, Ugalde C, Willems PH (2004) Cell biological consequences of mitochondrial NADH: ubiquinone oxidoreductase deficiency. Curr Neurovasc Res 1:29–40

    Article  CAS  PubMed  Google Scholar 

  9. Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (2003) Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 23:10756–10764

    CAS  PubMed  Google Scholar 

  10. Marshall LE, Himes RH (1978) Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta 543:590

    Article  CAS  PubMed  Google Scholar 

  11. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306

    Article  CAS  PubMed  Google Scholar 

  12. Ren Y, Liu W, Jiang H, Jiang Q, Feng J (2005) Selective vulnerability of dopaminergic neurons to microtubule depolymerisation. J Biol Chem 280:34105–34112

    Article  CAS  PubMed  Google Scholar 

  13. Feng Y, Liang ZH, Wang T, Qiao X, Liu HJ, Sun SG (2006) alpha-Synuclein redistributed and aggregated in rotenone-induced Parkinson’s disease rats. Neurosci Bull 22:288–293

    CAS  PubMed  Google Scholar 

  14. Mader BJ, Pivtoraiko VN, Flippo HM, Klocke BJ, Roth KA, Mangieri LR, Shacka JJ (2012) Rotenone inhibits autophagic flux prior to inducing cell death. ACS Chem Neurosci 3:1063–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arduíno DM, Esteves AR, Cortes L, Silva DF, Patel B, Grazina M, Swerdlow RH, Oliveira CR, Cardoso SM (2012) Mitochondrial metabolism in Parkinson’s disease impairs quality control autophagy by hampering microtubule-dependent traffic. Hum Mol Genet 21:4680–4702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ahmadi FA, Linseman DA, Grammatopoulos TN, Jones SM, Bouchard RJ, Freed CR, Heidenreich KA, Zawada WM (2003) The pesticide rotenone induces caspase-3-mediated apoptosis in ventral mesencephalic dopaminergic neurons. J Neurochem 87:914–921

    Article  CAS  PubMed  Google Scholar 

  17. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tada-Oikawa S, Hiraku Y, Kawanishi M, Kawanishi S (2003) Mechanism for generation of hydrogen peroxide and change of mitochondrial membrane potential during rotenone-induced apoptosis. Life Sci 73:3277–3288

    Article  CAS  PubMed  Google Scholar 

  19. Lim MLR, Mercer LD, Nagley P, Beart PM (2007) Rotenone and MPP + preferentially redistribute apoptosis-inducing factor in apoptotic dopamine neurons. Neuro Rep 18:307–312

    CAS  Google Scholar 

  20. Wu Y-N, Johnson SW (2007) Rotenone potentiates NMDA currents in substantia nigra dopamine neurons. Neurosci Lett 421:96–100

    Article  CAS  PubMed  Google Scholar 

  21. Wu Y-N, Johnson SW (2009) Rotenone reduces Mg2+−dependent block of NMDA currents in substantia nigra dopamine neurons. Neurotoxicology 30:320–325

    Article  PubMed  CAS  Google Scholar 

  22. Hongo H, Kihara T, Kume T, Izumi Y, Niidome T, Sugimoto H, Akaike A (2012) Glycogen synthase kinase-3β activation mediates rotenone-induced cytotoxicity with the involvement of microtubule destabilization. Biochem Biophys Res Commun 426:94–99

    Article  CAS  PubMed  Google Scholar 

  23. Köchl R, Hu XW, Chan EY, Tooze SA (2006) Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7:129–145

    Article  PubMed  CAS  Google Scholar 

  24. Liu XA, Rizzo V, Puthanveettil SV (2012) Pathologies of axonal transport in neurodegenerative diseases. Transl Neurosci 3:355–372

    Article  PubMed  PubMed Central  Google Scholar 

  25. Arduíno DM, Esteves AR, Cardoso SM (2013) Mitochondria drive autophagy pathology via microtubule disassembly: a new hypothesis for Parkinson disease. Autophagy 9:112–114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Esteves AR, Gozes I, Cardoso SM (2014) The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson’s disease. Biochim Biophys Acta 1842:7–21

    Article  CAS  PubMed  Google Scholar 

  27. Ding Q, Keller JN (2001) Proteasomes and proteasome inhibition in the central nervous system. Free Radic Biol Med 31:574–584

    Article  CAS  PubMed  Google Scholar 

  28. Grune T, Jung T, Merker K, Davies KJ (2004) Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease. Int J Biochem Cell Biol 36:2519–2530

    Article  CAS  PubMed  Google Scholar 

  29. Keller JN, Huang FF, Zhu H, Yu J, Ho YS, Kindy TS (2000) Oxidative stress-associated impairment of proteasome activity during ischemia-reperfusion injury. J Cereb Blood Flow Metab 20:1467–1473

    Article  CAS  PubMed  Google Scholar 

  30. Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439

    Article  CAS  PubMed  Google Scholar 

  31. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594

    Article  CAS  PubMed  Google Scholar 

  32. Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235:1641–1644

    Article  CAS  PubMed  Google Scholar 

  33. Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT (2012) The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 181:1426–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL (1999) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 8:673–682

    Article  CAS  PubMed  Google Scholar 

  35. McKinnon C, Tabrizi SJ (2004) The ubiquitin-proteasome system in neurodegeneration. Antioxid Redox Signal 21:2302–2321

    Article  CAS  Google Scholar 

  36. Fenteany G, Schreiber SL (1998) Lactacystin, proteasome function, and cell fate. J Biol Chem 273:8545–8548

    Article  CAS  PubMed  Google Scholar 

  37. Cheung NS, Choy MS, Halliwell B, Teo TS, Bay BH, Lee AY, Qi RZ, Koh VH, Whiteman M, Koay ES et al (2004) Lactacystin-induced apoptosis of cultured mouse cortical neurons is associated with accumulation of PTEN in the detergent-resistant membrane fraction. Cell Mol Life Sci 61:1926–1934

    Article  CAS  PubMed  Google Scholar 

  38. Li X, Du Y, Fan X, Yang D, Luo G, Le W (2008) c-Jun N-terminal kinase mediates lactacystin-induced dopamine neuron degeneration. J Neuropathol Exp Neurol 67:933–944

    Article  CAS  PubMed  Google Scholar 

  39. Choy MS, Chen MJ, Manikandan J, Peng ZF, Jenner AM, Melendez AJ, Cheung NS (2011) Up-regulation of endoplasmic reticulum stress-related genes during the early phase of treatment of cultured cortical neurons by the proteasomal inhibitor lactacystin. J Cell Physiol 226:494–510

    Article  CAS  PubMed  Google Scholar 

  40. Rideout HJ, Larsen KE, Sulzer D, Stefanis L (2001) Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. J Neurochem 78:899–908

    Article  CAS  PubMed  Google Scholar 

  41. Yew EH, Cheung NS, Choy MS, Qi RZ, Lee AY, Peng ZF, Melendez AJ, Manikandan J, Koay ES, Chiu LL, Ng WL, Whiteman M, Kandiah J, Halliwell B (2005) Proteasome inhibition by lactacystin in primary neuronal cells induces both potentially neuroprotective and pro-apoptotic transcriptional responses: a microarray analysis. J Neurochem 94:943–956

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Perez-Alvarez S, Solesio ME, Manzanares J, Jordán J, Galindo MF (2009) Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria-mediated cell death. Br J Pharmacol 158:1121–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qiu JH, Asai A, Chi S, Saito N, Hamada H, Kirino T (2000) Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci 20:259–265

    CAS  PubMed  Google Scholar 

  45. Du Y, Yang D, Li L, Luo G, Li T, Fan X, Wang Q, Zhang X, Wang Y, Le W (2009) An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity. Autophagy 5:663–675

    Article  CAS  PubMed  Google Scholar 

  46. Jantas D, Lorenc-Koci E, Kubera M, Lason W (2011) Neuroprotective effects of MAPK/ERK1/2 and calpain inhibitors on lactacystin-induced cell damage in primary cortical neurons. Neurotoxicology 32:845–856

    Article  CAS  PubMed  Google Scholar 

  47. Miura Y, Sakurai Y, Hayakawa M, Shimada Y, Zempel H, Sato Y, Hisanaga S, Endo T (2010) Translocation of lysosomal cathepsin D caused by oxidative stress or proteasome inhibition in primary cultured neurons and astrocytes. Biol Pharm Bull 33:22–28

    Article  CAS  PubMed  Google Scholar 

  48. Rideout HJ, Wang Q, Park DS, Stefanis L (2003) Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition. J Neurosci 23:1237–1245

    CAS  PubMed  Google Scholar 

  49. Demasi M, Davies KJ (2003) Proteasome inhibitors induce intracellular protein aggregation and cell death by an oxygen-dependent mechanism. FEBS Lett 542:89–94

    Article  CAS  PubMed  Google Scholar 

  50. Rockwell P, Yuan H, Magnusson R, Figueiredo-Pereira ME (2000) Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch Biochem Biophys 374:325–333

    Article  CAS  PubMed  Google Scholar 

  51. Sun F, Kanthasamy A, Song C, Yang Y, Anantharam V, Kanthasamy AG (2008) Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation. J Cell Mol Med 12:2467–2481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang Y, Qin ZH (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis 15:1382–1402

    Article  CAS  PubMed  Google Scholar 

  54. Spalloni A, Nutini M, Longone P (2013) Role of the N-methyl-d-aspartate receptors complex in amyotrophic lateral sclerosis. Biochim Biophys Acta 1832:312–322

    Article  CAS  PubMed  Google Scholar 

  55. Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719–721

    Article  CAS  PubMed  Google Scholar 

  56. Hara MR, Snyder SH (2007) Cell signaling and neuronal death. Annu Rev Pharmacol Toxicol 47:117–141

    Article  CAS  PubMed  Google Scholar 

  57. Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379

    CAS  PubMed  Google Scholar 

  58. Choi DW, Maulucci-Gedde M, Kriegstein AR (1987) Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368

    CAS  PubMed  Google Scholar 

  59. Choi DW, Koh JY, Peters S (1988) Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci 8:185–196

    CAS  PubMed  Google Scholar 

  60. Brewer LD, Thibault O, Staton J, Thibault V, Rogers JT, Garcia-Ramos G et al (2007) Increased vulnerability of hippocampal neurons with age in culture: temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels. Brain Res 1151:20–31

    Article  CAS  PubMed  Google Scholar 

  61. Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1:366–373

    Article  CAS  PubMed  Google Scholar 

  62. Stanika RI, Pivovarova NB, Brantner CA, Watts CA, Winters CA, Andrews SB (2009) Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Proc Natl Acad Sci USA 106:9854–9859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Starkov AA, Chinopoulos C, Fiskum G (2004) Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36:257–264

    Article  CAS  PubMed  Google Scholar 

  64. Ruiz A, Alberdi E, Matute C (2014) CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death Dis 5:e1156. doi:10.1038/cddis.2014.134

    Article  CAS  PubMed  Google Scholar 

  65. Wang H, Yu SW, Koh DW, Lew J, Coombs C, Bowers W, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2004) Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci 24:10963–10973

    Article  CAS  PubMed  Google Scholar 

  66. Verkhratsky A, Petersen OH (2002) The endoplasmic reticulum as an integrating signalling organelle: from neuronal signalling to neuronal death. Eur J Pharmacol 447:141–154

    Article  CAS  PubMed  Google Scholar 

  67. Paschen W, Mengesdorf T (2005) Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease–therapeutic potential. Pharmacol Ther 108:362–375

    Article  CAS  PubMed  Google Scholar 

  68. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389

    Article  CAS  PubMed  Google Scholar 

  69. Rameau GA, Chiu LY, Ziff EB (2003) NMDA receptor regulation of nNOS phosphorylation and induction of neuron death. Neurobiol Aging 24:1123–1133

    Article  CAS  PubMed  Google Scholar 

  70. Shi ZQ, Sunico CR, McKercher SR, Cui J, Feng GS, Nakamura T, Lipton SA (2013) S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke. Proc Natl Acad Sci USA 110:3137–3142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tang LJ, Li C, Hu SQ, Wu YP, Zong YY, Sun CC, Zhang F, Zhang GY (2012) S-nitrosylation of c-Src via NMDAR-nNOS module promotes c-Src activation and NR2A phosphorylation in cerebral ischemia/reperfusion. Mol Cell Biochem 365:363–377

    Article  CAS  PubMed  Google Scholar 

  72. de Murcia G, Schreiber V, Molinete M, Saulier B, Poch O, Masson M, Niedergang C, Ménissier de Murcia J (1994) Structure and function of poly(ADP-ribose) polymerase. Mol Cell Biochem 138:15–24

    Article  PubMed  Google Scholar 

  73. Springer JE, Azbill RD, Nottingham SA, Kennedy SE (2000) Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury. J Neurosci 20:7246–7251

    CAS  PubMed  Google Scholar 

  74. Maestre C, Delgado-Esteban M, Gomez-Sanchez JC, Bolaños JP, Almeida A (2008) Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity. EMBO J 27:2736–2745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolaños JP (2012) Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ 19:1582–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zyskind JW, Wang Y, Cho G, Ting JH, Kolson DL, Lynch DR, Jordan-Sciutto KL (2015) E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity. J Neurochem 132:742–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chiricozzi E, Fernandez-Fernandez S, Nardicchi V, Almeida A, Bolaños JP, Goracci G (2010) Group IIA secretory phospholipase A2 (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons. J Neurochem 112:1574–1583

    Article  CAS  PubMed  Google Scholar 

  78. Caldeira MV, Curcio M, Leal G, Salazar IL, Mele M, Santos AR, Melo CV, Pereira P, Canzoniero LM, Duarte CB (2013) Excitotoxic stimulation downregulates the ubiquitin-proteasome system through activation of NMDA receptors in cultured hippocampal neurons. Biochim Biophys Acta 1832:263–274

    Article  CAS  PubMed  Google Scholar 

  79. Sadasivan S, Zhang Z, Larner SF, Liu MC, Zheng W, Kobeissy FH, Hayes RL, Wang KK (2010) Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype. BMC Neurosci 11:21. doi:10.1186/1471-2202-11-21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Wang Y, Wang W, Li D, Li M, Wang P, Wen J, Liang M, Su B, Yin Y (2014) IGF-1 alleviates NMDA-induced excitotoxicity in cultured hippocampal neurons against autophagy via the NR2B/PI3 K-AKT-mTOR pathway. J Cell Physiol 229:1618–1629

    Article  CAS  PubMed  Google Scholar 

  81. Chen MJ, Ng JM, Peng ZF, Manikandan J, Yap YW, Llanos RM, Beart PM, Cheung NS (2013) Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: evidence favouring cell cycle re-activation in concert with oxidative stress. Neurochem Int 62:719–730

    Article  CAS  PubMed  Google Scholar 

  82. Efthimiadi L, Farso M, Quirion R, Krantic S (2012) Cyclin D1 induction preceding neuronal death via the excitotoxic NMDA pathway involves selective stimulation of extrasynaptic NMDA receptors and JNK pathway. Neurodegener Dis 10:80–91

    Article  CAS  PubMed  Google Scholar 

  83. Caldeira MV, Salazar IL, Curcio M, Canzoniero LM, Duarte CB (2014) Role of the ubiquitin-proteasome system in brain ischemia: friend or foe? Prog Neurobiol 112:50–69

    Article  CAS  PubMed  Google Scholar 

  84. Pérez-Carrión MD, Pérez-Martínez FC, Merino S, Sánchez-Verdú P, Martínez-Hernández J, Luján R, Ceña V (2012) Dendrimer-mediated siRNA delivery knocks down Beclin 1 and potentiates NMDA-mediated toxicity in rat cortical neurons. J Neurochem 120:259–268

    Article  PubMed  CAS  Google Scholar 

  85. Pérez-Carrión MD, Ceña V (2013) Knocking down HMGB1 using dendrimer-delivered siRNA unveils its key role in NMDA-induced autophagy in rat cortical neurons. Pharm Res 30:2584–2595

    Article  PubMed  CAS  Google Scholar 

  86. Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, Gu ZL, Qin ZH (2009) p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. Eur J Neurosci 30:2258–2270

    Article  PubMed  Google Scholar 

  87. Yap YW, Chen MJ, Peng ZF, Manikandan J, Ng JM, Llanos RM, La Fontaine S, Beart PM, Cheung NS (2013) Gene expression profiling of rotenone-mediated cortical neuronal death: evidence for inhibition of ubiquitin-proteasome system and autophagy–lysosomal pathway, and dysfunction of mitochondrial and calcium signaling. Neurochem Int 62:653–663

    Article  CAS  PubMed  Google Scholar 

  88. Llorente-Folch I, Rueda CB, Pardo B, Szabadkai G, Duchen MR, Satrustegui J (2015) The regulation of neuronal mitochondrial metabolism by calcium. J Physiol. doi:10.1113/JP270254

  89. Santo-Domingo J, Demaurex N (2010) Calcium uptake mechanisms of mitochondria. BBA Bioenerg 1797:907–912

    Article  CAS  Google Scholar 

  90. Tanaka K, Matsuda N (2014) Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. BBA Mol Cell Res 1843:197–204

    CAS  Google Scholar 

  91. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, Han F, Fukunaga K, Qin ZH (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 

  94. Nah J, Yuan J, Jung YK (2015) Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol Cells 38:381–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JB et al (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686–699

    Article  PubMed  PubMed Central  Google Scholar 

  96. Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Brady OA, Zheng Y, Murphy K, Huang M, Hu F (2013) The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 22:685–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Janda E, Isidoro C, Carresi C, Mollace V (2012) Defective autophagy in Parkinson’s disease: role of oxidative stress. Mol Neurobiol 46:639–661

    Article  CAS  PubMed  Google Scholar 

  99. Diaz-Corrales FJ, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N (2005) Rotenone induces aggregation of gamma-tubulin protein and subsequent disorganization of the centrosome: relevance to formation of inclusion bodies and neurodegeneration. Neuroscience 133:117–135

    Article  CAS  PubMed  Google Scholar 

  100. Dugan LL, Sensi SL, Canzoniero LM, Handran SD, Rothman SM, Lin TS, Goldberg MP, Choi DW (1995) Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. J Neurosci 15:6377–6388

    CAS  PubMed  Google Scholar 

  101. Reynolds IJ, Hastings TG (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 15:3318–3327

    CAS  PubMed  Google Scholar 

  102. Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12:857–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M (1999) Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284:1845–1848

    Article  CAS  PubMed  Google Scholar 

  104. Mytilineou C, McNaught KS, Shashidharan P, Yabut J, Baptiste RJ, Parnandi A, Olanow CW (2004) Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress. J Neural Transm 111:1237–1251

    Article  CAS  PubMed  Google Scholar 

  105. Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W (2008) Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 32:16–25

    Article  CAS  PubMed  Google Scholar 

  106. B’chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A (2013) The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res 41:7683–7699

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Abreu M, Sealy L (2012) Cells expressing the C/EBPbeta isoform, LIP, engulf their neighbours. PLoS ONE 7:e41807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lin TK, Chen SD, Chuang YC, Lin HY, Huang CR, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Liou CW (2014) Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci 15:1625–1646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Zhao W, Li Y, Jia L, Pan L, Li H, Du J (2014) Atg5 deficiency-mediated mitophagy aggravates cardiac inflammation and injury in response to angiotensin II. Free Radic Biol Med 69:108–115

    Article  CAS  PubMed  Google Scholar 

  110. Liang A, Wang Y, Woodard LE, Wilson MH, Sharma R, Awasthi YC, Du J, Mitch WE, Cheng J (2012) Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis. J Pathol 228:448–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Baird SK, Kurz T, Brunk UT (2006) Metallothionein protects against oxidative stress-induced lysosomal destabilization. Biochem J 394:275–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV (2014) Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun 5:3496

    PubMed  PubMed Central  Google Scholar 

  113. Gordon PB, Holen I, Fosse M, Røtnes JS, Seglen PO (1993) Dependence of hepatocytic autophagy on intracellularly sequestered calcium. J Biol Chem 268:26107–26112

    CAS  PubMed  Google Scholar 

  114. Cárdenas C, Miller RA, Smith I, Bui T, Molgó J, Müller M, Vais H, Cheung KH, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR, Foskett JK (2010) Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142:270–283

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Hansen K, Wagner B, Hamel W, Schweizer M, Haag F, Westphal M, Lamszus K (2007) Autophagic cell death induced by TrkA receptor activation in human glioblastoma cells. J Neurochem 103:259–275

    CAS  PubMed  Google Scholar 

  116. Høyer-Hansen M, Jäättelä M (2007) AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 3:381–383

    Article  PubMed  Google Scholar 

  117. Bakker AC, Webster P, Jacob WA, Andrews NW (1997) Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts. J Cell Sci 110:2227–2238

    CAS  PubMed  Google Scholar 

  118. McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425

    CAS  PubMed  Google Scholar 

  119. Rodríguez A, Webster P, Ortego J, Andrews NW (1997) Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J Cell Biol 137:93–104

    Article  PubMed  PubMed Central  Google Scholar 

  120. Ghislat G, Knecht E (2013) Ca2+-sensor proteins in the autophagic and endocytic traffic. Curr Protein Pept Sci 14:97–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ryu HW, Oh WK, Jang IS, Park J (2013) Amurensin G induces autophagy and attenuates cellular toxicities in a rotenone model of Parkinson’s disease. Biochem Biophys Res Commun 433:121–126

    Article  CAS  PubMed  Google Scholar 

  122. Deng YN, Shi J, Liu J, Qu QM (2013) Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int 63:1–9

    Article  CAS  PubMed  Google Scholar 

  123. Gao H, Yang W, Qi Z, Lu L, Duan C, Zhao C, Yang H (2012) DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy. J Mol Biol 423:232–248

    Article  CAS  PubMed  Google Scholar 

  124. Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, Rotilio G, Ciriolo MR (2012) Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson’s disease. Neurobiol Aging 33:767–785

    Article  CAS  PubMed  Google Scholar 

  125. Giordano S, Dodson M, Ravi S, Redmann M, Ouyang X, Darley Usmar VM, Zhang J (2014) Bioenergetic adaptation in response to autophagy regulators during rotenone exposure. J Neurochem 131:625–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  127. Xiong N, Jia M, Chen C, Xiong J, Zhang Z, Huang J, Hou L, Yang H, Cao X, Liang Z, Sun S, Lin Z, Wang T (2011) Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y. Neuroscience 199:292–302

    Article  CAS  PubMed  Google Scholar 

  128. Pérez-Carrión MD, Pérez-Martínez FC, Merino S, Sánchez-Verdú P, Martínez-Hernández J, Luján R, Ceña V (2012) Dendrimer-mediated siRNA delivery knocks down Beclin 1 and potentiates NMDA-mediated toxicity in rat cortical neurons. J Neurochem 120:259–268

    Article  PubMed  CAS  Google Scholar 

  129. Emans N, Gorvel JP, Walter C, Gerke V, Kellner R, Griffiths G, Gruenberg J (1993) Annexin II is a major component of fusogenic endosomal vesicles. J Cell Biol 120:1357–1369

    Article  CAS  PubMed  Google Scholar 

  130. Ghislat G, Aguado C, Knecht E (2012) Annexin A5 stimulates autophagy and inhibits endocytosis. J Cell Sci 125:92–107

    Article  CAS  PubMed  Google Scholar 

  131. Friedman LG, Qureshi YH, Yu WH (2015) Promoting autophagic clearance: viable therapeutic targets in Alzheimer’s disease. Neurotherapeutics 12:94–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Spuch C, Ortolano S, Navarro C (2012) New insights in the amyloid-Beta interaction with mitochondria. J Aging Res 2012:324968

    Article  PubMed  PubMed Central  Google Scholar 

  133. Schon EA, Area-Gomez E (2010) Is Alzheimer’s disease a disorder of mitochondria-associated membranes? J Alzheimers Dis 20(Suppl 2):S281–S292

    PubMed  Google Scholar 

  134. Devi L, Anandatheerthavarada HK (2010) Mitochondrial trafficking of APP and alpha synuclein: relevance to mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases. Biochim Biophys Acta 1802:11–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TW, Shen J, Slack RS, Park DS (2012) ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet 21:4888–4903

    Article  CAS  PubMed  Google Scholar 

  137. Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Niu J, Yu M, Wang C, Xu Z (2012) Leucine-rich repeat kinase2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem 122:650–658

    Article  CAS  PubMed  Google Scholar 

  139. Wang X, Yan MH, Fujioka H, Liu J, Wilson-Delfosse A, Chen SG, Perry G, Casadesus G, Zhu X (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 21:1931–1944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li W, Srinivasula SM, Chai J, Li P, Wu JW, Zhang Z, Alnemri ES, Shi Y (2002) Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat Struct Biol 9:436–441

    Article  CAS  PubMed  Google Scholar 

  141. Shi P, Gal J, Kwinter DM, Liu X, Zhu H (2010) Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim Biophys Acta 1802:45–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Oliveira JM (2010) Nature and cause of mitochondrial dysfunction in Huntington’s disease: focusing on huntingtin and the striatum. J Neurochem 114:1–12

    CAS  PubMed  Google Scholar 

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Acknowledgments

PMB were supported a NHMRC Research Fellowship (APP1019833). The Florey Institute of Neuroscience and Mental Health receives infrastructure support from the Victorian State Government (Australia).

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Authors and Affiliations

  1. Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, VIC, 3125, Australia

    Yann Wan Yap, Roxana M. Llanos, Sharon La Fontaine, Michael A. Cater & Nam Sang Cheung

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3052, Australia

    Sharon La Fontaine & Philip M. Beart

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  1. Yann Wan Yap
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Correspondence to Nam Sang Cheung.

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Special Issue: In honor of Dr. Philip Beart.

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Yap, Y.W., Llanos, R.M., La Fontaine, S. et al. Comparative Microarray Analysis Identifies Commonalities in Neuronal Injury: Evidence for Oxidative Stress, Dysfunction of Calcium Signalling, and Inhibition of Autophagy–Lysosomal Pathway. Neurochem Res 41, 554–567 (2016). https://doi.org/10.1007/s11064-015-1666-2

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