 |
||||
|
||||
|
||||
|
||||
The Journal of Neuroscience, May 15, 2003, 23(10):4081-4091
Previous Article | Next Article
Inhibition of Calpains Prevents Neuronal and Behavioral Deficits in an MPTP Mouse Model of Parkinson's Disease
Stephen J. Crocker,1 Patrice D. Smith,1 Vernice Jackson-Lewis,3 Wiplore R. Lamba,1 Shawn P. Hayley,1 Erich Grimm,5 Steve M. Callaghan,1 Ruth S. Slack,1 Edon Melloni,7 Serge Przedborski,3,4 George S. Robertson,6 Hymie Anisman,8 Zul Merali,2 andDavid S. Park1 1Neuroscience Research Group, Ottawa Health Research Institute, 2Department of Psychology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, 3Department of Neurology, Center for Neurobiology and Behaviour, Columbia University, New York, New York 10032, 4Department of Pathology, Center for Neurobiology and Behaviour, Columbia University, New York, New York 10032, 5Department of Chemistry, Merck-Frosst and Company Canada Inc., Kirkland, Quebec H9H 3L1, Canada, 6Department of Pharmacology, Merck-Frosst and Company Canada Inc., Kirkland, Quebec H9H 3L1, Canada, 7Department of Experimental Medicine, University of Genoa, 1-16132 Genoa, Italy, and 8Institute for Neuroscience, Carleton University, Ottawa K1H 6N5, Canada
The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement of the calcium-dependent proteases, calpains, in the loss of dopamine neurons in a mouse model of PD. We show that administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neurons in vivo. Inhibition of calpain proteolysis using either a calpain inhibitor (MDL-28170) or adenovirus-mediated overexpression of the endogenous calpain inhibitor protein, calpastatin, significantly attenuated MPTP-induced loss of nigral dopamine neurons. Commensurate with this neuroprotection, MPTP-induced locomotor deficits were abolished, and markers of striatal postsynaptic activity were normalized in calpain inhibitor-treated mice. However, behavioral improvements in MPTP-treated, calpain inhibited mice did not correlate with restored levels of striatal dopamine. These results suggest that protection against nigral neuron degeneration in PD may be sufficient to facilitate normalized locomotor activity without necessitating striatal reinnervation. Immunohistochemical analyses of postmortem midbrain tissues from human PD cases also displayed evidence of increased calpain-related proteolytic activity that was not evident in age-matched control subjects. Taken together, our findings provide a potentially novel correlation between calpain proteolytic activity in an MPTP model of PD and the etiology of neuronal loss in PD in humans.
Key words: substantia nigra; dopamine; neurotensin; FosB; protease; adenovirus; behavior; L-Dopa
Received Dec. 26, 2002; revised Mar. 7, 2003; accepted Mar. 17, 2003.
This article has been cited by other articles:
J. Liu, M. C. Liu, and K. K. W. Wang
Calpain in the CNS: From Synaptic Function to Neurotoxicity
Sci. Signal., April 8, 2008; 1(14): re1 - re1.
[Abstract] [Full Text] [PDF]
T. Kawasaki, K. Ishihara, Y. Ago, A. Baba, and T. Matsuda
Edaravone (3-Methyl-1-phenyl-2-pyrazolin-5-one), a Radical Scavenger, Prevents 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Neurotoxicity in the Substantia Nigra but Not the Striatum
J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 274 - 281.
[Abstract] [Full Text] [PDF]
B. M. Dufty, L. R. Warner, S. T. Hou, S. X. Jiang, T. Gomez-Isla, K. M. Leenhouts, J. T. Oxford, M. B. Feany, E. Masliah, and T. T. Rohn
Calpain-Cleavage of {alpha}-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation
Am. J. Pathol., May 1, 2007; 170(5): 1725 - 1738.
[Abstract] [Full Text] [PDF]
M. P. Mount, A. Lira, D. Grimes, P. D. Smith, S. Faucher, R. Slack, H. Anisman, S. Hayley, and D. S. Park
Involvement of Interferon-{gamma} in Microglial-Mediated Loss of Dopaminergic Neurons
J. Neurosci., March 21, 2007; 27(12): 3328 - 3337.
[Abstract] [Full Text] [PDF]
M. Averna, R. Stifanese, R. De Tullio, M. Passalacqua, E. Defranchi, F. Salamino, E. Melloni, and S. Pontremoli
Regulation of Calpain Activity in Rat Brain with Altered Ca2+ Homeostasis
J. Biol. Chem., January 26, 2007; 282(4): 2656 - 2665.
[Abstract] [Full Text] [PDF]
S. J. Crocker, J. K. Whitmire, R. F. Frausto, P. Chertboonmuang, P. D. Soloway, J. L. Whitton, and I. L. Campbell
Persistent Macrophage/Microglial Activation and Myelin Disruption after Experimental Autoimmune Encephalomyelitis in Tissue Inhibitor of Metalloproteinase-1-Deficient Mice
Am. J. Pathol., December 1, 2006; 169(6): 2104 - 2116.
[Abstract] [Full Text] [PDF]
S. T. Hou, S. X. Jiang, A. Desbois, D. Huang, J. Kelly, L. Tessier, L. Karchewski, and J. Kappler
Calpain-cleaved collapsin response mediator protein-3 induces neuronal death after glutamate toxicity and cerebral ischemia.
J. Neurosci., February 22, 2006; 26(8): 2241 - 2249.
[Abstract] [Full Text] [PDF]
P. D. Smith, M. P. Mount, R. Shree, S. Callaghan, R. S. Slack, H. Anisman, I. Vincent, X. Wang, Z. Mao, and D. S. Park
Calpain-Regulated p35/cdk5 Plays a Central Role in Dopaminergic Neuron Death through Modulation of the Transcription Factor Myocyte Enhancer Factor 2
J. Neurosci., January 11, 2006; 26(2): 440 - 447.
[Abstract] [Full Text] [PDF]
J. Arredondo, A. I. Chernyavsky, A. Karaouni, and S. A. Grando
Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus
Am. J. Pathol., December 1, 2005; 167(6): 1531 - 1544.
[Abstract] [Full Text] [PDF]
F. Zoccarato, P. Toscano, and A. Alexandre
Dopamine-derived Dopaminochrome Promotes H2O2 Release at Mitochondrial Complex I: STIMULATION BY ROTENONE, CONTROL BY Ca2+, AND RELEVANCE TO PARKINSON DISEASE
J. Biol. Chem., April 22, 2005; 280(16): 15587 - 15594.
[Abstract] [Full Text] [PDF]
J. Takano, M. Tomioka, S. Tsubuki, M. Higuchi, N. Iwata, S. Itohara, M. Maki, and T. C. Saido
Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains: EVIDENCE FROM CALPASTATIN MUTANT MICE
J. Biol. Chem., April 22, 2005; 280(16): 16175 - 16184.
[Abstract] [Full Text] [PDF]
M. Higuchi, M. Tomioka, J. Takano, K. Shirotani, N. Iwata, H. Masumoto, M. Maki, S. Itohara, and T. C. Saido
Distinct Mechanistic Roles of Calpain and Caspase Activation in Neurodegeneration as Revealed in Mice Overexpressing Their Specific Inhibitors
J. Biol. Chem., April 15, 2005; 280(15): 15229 - 15237.
[Abstract] [Full Text] [PDF]
R. H. Kim, P. D. Smith, H. Aleyasin, S. Hayley, M. P. Mount, S. Pownall, A. Wakeham, A. J. You-Ten, S. K. Kalia, P. Horne, et al.
Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress
PNAS, April 5, 2005; 102(14): 5215 - 5220.
[Abstract] [Full Text] [PDF]
B. M. Polster, G. Basanez, A. Etxebarria, J. M. Hardwick, and D. G. Nicholls
Calpain I Induces Cleavage and Release of Apoptosis-inducing Factor from Isolated Mitochondria
J. Biol. Chem., February 25, 2005; 280(8): 6447 - 6454.
[Abstract] [Full Text] [PDF]
E. Keramaris, J. L. Vanderluit, M. Bahadori, K. Mousavi, R. J. Davis, R. Flavell, R. S. Slack, and D. S. Park
c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation
J. Biol. Chem., January 14, 2005; 280(2): 1132 - 1141.
[Abstract] [Full Text] [PDF]
R. Lowe, D. L. Pountney, P. H. Jensen, W. P. Gai, and N. H. Voelcker
Calcium(II) selectively induces {alpha}-synuclein annular oligomers via interaction with the C-terminal domain
Protein Sci., December 1, 2004; 13(12): 3245 - 3252.
[Abstract] [Full Text] [PDF]
S. Hayley, S. J. Crocker, P. D. Smith, T. Shree, V. Jackson-Lewis, S. Przedborski, M. Mount, R. Slack, H. Anisman, and D. S. Park
Regulation of Dopaminergic Loss by Fas in a 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease
J. Neurosci., February 25, 2004; 24(8): 2045 - 2053.
[Abstract] [Full Text] [PDF]
Q. Guo
Cyclin-Dependent Kinase 5--A Neuronal Killer?
Sci. Aging Knowl. Environ., December 17, 2003; 2003(50): pe36 - 36.
[Abstract] [Full Text]
P. D. Smith, S. J. Crocker, V. Jackson-Lewis, K. L. Jordan-Sciutto, S. Hayley, M. P. Mount, M. J. O'Hare, S. Callaghan, R. S. Slack, S. Przedborski, et al.
Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease
PNAS, November 11, 2003; 100(23): 13650 - 13655.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|