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The Journal of Neuroscience, May 15, 2003, 23(10):4081-4091
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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.
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