Inhibition of Calpains Prevents Neuronal and Behavioral Deficits in an MPTP Mouse Model of Parkinson's Disease

• DOI: 10.1523/jneurosci.23-10-04081.2003
• Publication Date: 2018-04-13T22:30:28Z
• Authors: Stephen J. Crocker; Patrice D. Smith; Vernice Jackson-L...; 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
• Keywords: MPTP

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 calcium-dependent proteases, calpains, loss mouse model PD. We show that administration N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase calpain-mediated proteolysis nigral vivo. Inhibition calpain using either inhibitor (MDL-28170) or adenovirus-mediated overexpression endogenous protein, calpastatin, significantly attenuated MPTP-induced neurons. Commensurate with this neuroprotection, locomotor deficits were abolished, and markers striatal postsynaptic activity normalized inhibitor-treated mice. However, behavioral improvements MPTP-treated, inhibited mice did not correlate restored levels dopamine. These results suggest protection against neuron PD may be sufficient facilitate without necessitating reinnervation. Immunohistochemical analyses postmortem tissues from human cases also displayed increased calpain-related proteolytic was evident age-matched control subjects. Taken together, our findings potentially novel correlation between MPTP etiology neuronal humans.