Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease.
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.
Crocker
Stephen J
SJ
Neuroscience Research Group, Ottawa Health Research Institute, Canada.
Smith
Patrice D
PD
Jackson-Lewis
Vernice
V
Lamba
Wiplore R
WR
Hayley
Shawn P
SP
Grimm
Erich
E
Callaghan
Steve M
SM
Slack
Ruth S
RS
Melloni
Edon
E
Przedborski
Serge
S
Robertson
George S
GS
Anisman
Hymie
H
Merali
Zul
Z
Park
David S
DS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology* / Q000517:prevention & control*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D011863:Radioimmunoassay / Q000379:methods; D020955:Striatonigral Degeneration / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000276:immunology / Q000378:metabolism
D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D016760:Proto-Oncogene Proteins c-fos; C033668:calpastatin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D002154:Calpain; D002118:Calcium; C058076:calpain inhibitor III