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Inhibition of Calpains Prevents Neuronal and Behavioral Deficits in an MPTP Mouse Model of Parkinson's Disease
- Source :
- The Journal of Neuroscience. 23:4081-4091
- Publication Year :
- 2003
- Publisher :
- Society for Neuroscience, 2003.
-
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 ofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neuronsin 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.
- Subjects :
- Male
Parkinson's disease
Tyrosine 3-Monooxygenase
Genetic Vectors
Radioimmunoassay
Substantia nigra
Cysteine Proteinase Inhibitors
Neuroprotection
Adenoviridae
Striatonigral Degeneration
Mice
chemistry.chemical_compound
Dopamine
medicine
Animals
Humans
Aged
Aged, 80 and over
Behavior, Animal
biology
Calpain
General Neuroscience
MPTP
Calcium-Binding Proteins
Excitatory Postsynaptic Potentials
Parkinson Disease
Dipeptides
Middle Aged
medicine.disease
Mice, Inbred C57BL
Substantia Nigra
Disease Models, Animal
medicine.anatomical_structure
nervous system
chemistry
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
biology.protein
Calcium
Neuron
Proto-Oncogene Proteins c-fos
Neuroscience
Injections, Intraperitoneal
Cellular/Molecular
medicine.drug
FOSB
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....181be31547c88c7bc700d305e89a49ca