Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection.

Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.

Constitutive expression and functional characterization of mitochondrial glutaredoxin (Grx2) in mouse and human brain.

Oxidative stress and mitochondrial dysfunction caused by loss of complex I activity are presumed to be primary events leading to neurodegeneration in Parkinson's disease. Mitochondrial glutaredoxin (Grx2), a glutathione-dependent thiol disulfide oxidoreductase helps maintain redox homeostasis in the mitochondria. We therefore, examined the constitutive expression of Grx2 in brain and its role in MPTP-mediated mitochondrial dysfunction in the extrapyramidal system. Grx2 is constitutively expressed in both neuron and glia in mouse and human brain including the neurons in human substantia nigra. Grx2 mRNA and protein were transiently upregulated in midbrain and striatum 1 h but not 4 h after a single dose of MPTP. Downregulation of Grx2 using antisense oligonucleotides, in vivo, in mouse brain resulted in partial loss of complex I activity indicating that Grx2 may help maintain complex I function in the mitochondria. Further, overexpression of Grx2 abolished MPP(+)-mediated toxicity in vitro in neuroblastoma cells. Our results demonstrate the probable role of Grx2 in maintenance of the redox milieu in mitochondria and its potential neuroprotective role in preserving mitochondrial integrity in neurodegenerative diseases, such as Parkinson's disease.