Abstract
The evidence implicating a mode of cell death that either favors or argues against caspase-dependent apoptosis is available in studies that used experimental models of Parkinson’s disease. We sought to investigate the mechanisms by which release of cytochrome c is not linked to caspase activation during rotenone-induced dopaminergic (DA) neurodegeneration. Unlike caspase activation in 6-hydroxydopamine-treated cells, both MN9D DA neuronal cells and primary cultures of mesencephalic neurons showed no obvious signs of caspase activation upon exposure to rotenone. We found that intracellular levels of ATP significantly decreased at the early phase of neurodegeneration (<~24 h) and therefore external addition of ATP to the lysates obtained at this stage reconstituted caspase-3 activity. At a later phase of cell death (>~24 h), both decreased levels of ATP and procaspase-9 contributed to the lack of caspase-3 activation. Under this condition, calpain and the proteasome system were responsible for the degradation of procaspase-9. Consequently, external addition of ATP and procaspase-9 to the lysates harvested at the later phase was required for activation of caspase-3. Similarly, caspase-3 activity was also reconstituted in the lysates harvested from cells co-treated with inhibitors of these proteases and incubated in the presence of external ATP. Taken together, our findings provided a sequential mechanism underlying how DA neurons may undergo caspase-independent cell death, even in the presence of cytoplasmic cytochrome c following inhibition of mitochondrial complex I.
Similar content being viewed by others
References
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909
Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87
Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6(4):304–312
Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5(1):107–110
Bloem BR, Irwin I, Buruma OJ, Haan J, Roos RA, Tetrud JW, Langston JW (1990) The MPTP model: versatile contributions to the treatment of idiopathic Parkinson’s disease. J Neurol Sci 97(2–3):273–293
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(12):1301–1306
Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, Jackson S, Gille G, Spillantini MG, Reichmann H, Funk RH (2010) Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE 5(1):e8762
Coulom H, Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24(48):10993–10998
Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 22(24):10690–10698
Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT (2002) An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 22(16):7006–7015
Viswanath V, Wu Y, Boonplueang R, Chen S, Stevenson FF, Yantiri F, Yang L, Beal MF, Andersen JK (2001) Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease. J Neurosci 21(24):9519–9528
Bilsland J, Roy S, Xanthoudakis S, Nicholson DW, Han Y, Grimm E, Hefti F, Harper SJ (2002) Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons. J Neurosci 22(7):2637–2649
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(4):914–921
Choi WS, Yoon SY, Oh TH, Choi EJ, O’Malley KL, Oh YJ (1999) Two distinct mechanisms are involved in 6-hydroxydopamine- and MPP+-induced dopaminergic neuronal cell death: role of caspases, ROS, and JNK. J Neurosci Res 57(1):86–94
Lotharius J, Dugan LL, O’Malley KL (1999) Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J Neurosci 19(4):1284–1293
Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S (1995) Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4(3):257–269
Han BS, Hong HS, Choi WS, Markelonis GJ, Oh TH, Oh YJ (2003) Caspase-dependent and -independent cell death pathways in primary cultures of mesencephalic dopaminergic neurons after neurotoxin treatment. J Neurosci 23(12):5069–5078
Li J, Spletter ML, Johnson DA, Wright LS, Svendsen CN, Johnson JA (2005) Rotenone-induced caspase 9/3-independent and -dependent cell death in undifferentiated and differentiated human neural stem cells. J Neurochem 92(3):462–476
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489
Kim HE, Yoon SY, Lee JE, Choi WS, Jin BK, Oh TH, Markelonis GJ, Chun SY, Oh YJ (2001) MPP(+) downregulates mitochondrially encoded gene transcripts and their activities in dopaminergic neuronal cells: protective role of Bcl-2. Biochem Biophys Res Commun 286(3):659–665
Xiong N, Huang J, Zhang Z, Xiong J, Liu X, Jia M, Wang F, Chen C, Cao X, Liang Z, Sun S, Lin Z, Wang T (2009) Stereotaxical infusion of rotenone: a reliable rodent model for Parkinson’s disease. PLoS ONE 4(11):e7878
Riedl SJ, Salvesen GS (2007) The apoptosome: signalling platform of cell death. Natl Rev Mol Cell Biol 8(5):405–413
Yokota M, Saido TC, Tani E, Kawashima S, Suzuki K (1995) Three distinct phases of fodrin proteolysis induced in postischemic hippocampus. Involvement of calpain and unidentified protease. Stroke 26(10):1901–1907
Von Ahsen O, Waterhouse NJ, Kuwana T, Newmeyer DD, Green DR (2000) The ‘harmless’ release of cytochrome c. Cell Death Differ 7(12):1192–1199
Borutaite V, Brown GC (2007) Mitochondrial regulation of caspase activation by cytochrome oxidase and tetramethylphenylenediamine via cytosolic cytochrome c redox state. J Biol Chem 282(43):31124–31130
Vaughn AE, Deshmukh M (2008) Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 10(12):1477–1483
Torok NJ, Higuchi H, Bronk S, Gores GJ (2002) Nitric oxide inhibits apoptosis downstream of cytochrome c release by nitrosylating caspase 9. Cancer Res 62(6):1648–1653
Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5(7):647–654
Zech B, Kohl R, von Knethen A, Brune B (2003) Nitric oxide donors inhibit formation of the Apaf-1/caspase-9 apoptosome and activation of caspases. Biochem J 371(Pt 3):1055–1064
Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83(3):731–801
Vosler PS, Brennan CS, Chen J (2008) Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol Neurobiol 38(1):78–100
Iacopino AM, Rhoten WB, Christakos S (1990) Calcium binding protein (calbindin-D28k) gene expression in the developing and aging mouse cerebellum. Brain Res Mol Brain Res 8(4):283–290
Mouatt-Prigent A, Karlsson JO, Agid Y, Hirsch EC (1996) Increased M-calpain expression in the mesencephalon of patients with Parkinson’s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neuroscience 73(4):979–987
Crocker SJ, Smith PD, Jackson-Lewis V, Lamba WR, Hayley SP, Grimm E, Callaghan SM, Slack RS, Melloni E, Przedborski S, Robertson GS, Anisman H, Merali Z, Park DS (2003) Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J Neurosci 23(10):4081–4091
Chua BT, Guo K, Li P (2000) Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases. J Biol Chem 275(7):5131–5135
Sharma AK, Rohrer B (2004) Calcium-induced calpain mediates apoptosis via caspase-3 in a mouse photoreceptor cell line. J Biol Chem 279(34):35564–35572
Lankiewicz S, Marc Luetjens C, Truc Bui N, Krohn AJ, Poppe M, Cole GM, Saido TC, Prehn JH (2000) Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death. J Biol Chem 275(22):17064–17071
Pang Z, Bondada V, Sengoku T, Siman R, Geddes JW (2003) Calpain facilitates the neuron death induced by 3-nitropropionic acid and contributes to the necrotic morphology. J Neuropathol Exp Neurol 62(6):633–643
Neumar RW, Xu YA, Gada H, Guttmann RP, Siman R (2003) Cross-talk between calpain and caspase proteolytic systems during neuronal apoptosis. J Biol Chem 278(16):14162–14167
Harbison RA, Ryan KR, Wilkins HM, Schroeder EK, Loucks FA, Bouchard RJ, Linseman DA (2011) Calpain plays a central role in 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in cerebellar granule neurons. Neurotoxic Res 19(3):374–388
Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13(7):805–811
Acknowledgments
This work was supported by a grant from the Ministry of Science and Technology through the Brain Research Center (Infra-2) and, in part, by the Mid-Career Research Program through the NRF funded by the MEST and by the KOSEF (SRC, Neurodegeneration Control Research Center at Kyung Hee University, the initial grant number R33-2008-036).
Author information
Authors and Affiliations
Corresponding author
Additional information
HeeWon Kang, Baek-Soo Han, and Su-Jeong Kim contributed equally to this article.
Rights and permissions
About this article
Cite this article
Kang, H., Han, BS., Kim, SJ. et al. Mechanisms to prevent caspase activation in rotenone-induced dopaminergic neurodegeneration: role of ATP depletion and procaspase-9 degradation. Apoptosis 17, 449–462 (2012). https://doi.org/10.1007/s10495-012-0699-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-012-0699-0