Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.
Incidence of Parkinson's disease is lower in women as compared with men. Although neuroprotective effect of estrogen is recognized, the underlying molecular mechanisms are unclear. MPTP (1-methyl-4-phenyl-1, 2, 3, 6, tetrahydro-pyridine), a neurotoxin that causes Parkinson's disease-like symptoms acts through inhibition of mitochondrial complex I. Administration of MPTP to male mice results in loss of dopaminergic neurons in substantia nigra, whereas female mice are unaffected. Oxidation of critical thiol groups by MPTP disrupts mitochondrial complex I, and up-regulation of glutaredoxin (a thiol disulfide oxidoreductase) is essential for recovery of complex I. Early events following MPTP exposure, such as increased AP1 transcription, loss of glutathione, and up-regulation of glutaredoxin mRNA is seen only in male mice, indicating that early response to neurotoxic insult does not occur in females. Pretreatment of female mice with ICI 182,780, estrogen receptor (ER) antagonist sensitizes them to MPTP-mediated complex I dysfunction. Constitutive expression of glutaredoxin is significantly higher in female mice as compared with males. ICI 182,780 down-regulates glutaredoxin activity in female mouse brain regions (midbrain and striatum), indicating that glutaredoxin expression is regulated through estrogen receptor signaling. Higher constitutive expression of glutaredoxin could potentially contribute to the neuroprotection seen in female mouse following exposure to neurotoxins, such as MPTP.
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