Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease

Stephen J. Crocker, Patrice D. Smith, Vernice Jackson-Lewis, Wiplore R. Lamba, Shawn P. Hayley, Erich Grimm, Steve M. Callaghan, Ruth S. Slack, Edon Melloni, Serge Przedborski, George S. Robertson, Hymie Anisman, Zul Merali, David S. Park

Research output: Contribution to journalArticlepeer-review

253 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4081-4091
Number of pages11
JournalJournal of Neuroscience
Volume23
Issue number10
DOIs
Publication statusPublished - 15 May 2003
Externally publishedYes

Keywords

  • Adenovirus
  • Behavior
  • Dopamine
  • FosB
  • L-Dopa
  • Neurotensin
  • Protease
  • Substantia nigra

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