Alteration in glutathione content and associated enzyme activities in the synaptic terminals but not in the non-synaptic mitochondria from the frontal cortex of Parkinson's disease brains.
Altered redox dynamics contribute to physiological aging and Parkinson's disease (PD). This is reflected in the substantia nigra (SN) of PD patients as lowered antioxidant levels and elevated oxidative damage. Contrary to this observation, we previously reported that non-SN regions such as caudate nucleus and frontal cortex (FC) exhibited elevated antioxidants and lowered mitochondrial and oxidative damage indicating constitutive protective mechanisms in PD brains. To investigate whether the sub-cellular distribution of antioxidants could contribute to these protective effects, we examined the distribution of antioxidant/oxidant markers in the neuropil fractions [synaptosomes, non-synaptic mitochondria and cytosol] of FC from PD (n = 9) and controls (n = 8). In the control FC, all the antioxidant activities [Superoxide dismutase (SOD), glutathione (GSH), GSH peroxidase (GPx), GSH-S-transferase (GST)] except glutathione reductase (GR) were the highest in cytosol, but several fold lower in mitochondria and much lower in synaptosomes. However, FC synaptosomes from PD brains had significantly higher levels of GSH (p = 0.01) and related enzymes [GPx (p = 0.02), GR (p = 0.06), GST (p = 0.0001)] compared to controls. Conversely, mitochondria from the FC of PD cases displayed elevated SOD activity (p = 0.02) while the GSH and related enzymes were relatively unaltered. These changes in the neuropil fractions were associated with unchanged or lowered oxidative damage. Further, the mitochondrial content in the synaptosomes of both PD and control brains was ≥five-fold lower compared to the non-synaptic mitochondrial fraction. Altered distribution of oxidant/antioxidant markers in the neuropil fractions of the human brain during aging and PD has implications for (1) degenerative and protective mechanisms (2) distinct antioxidant mechanisms in synaptic terminals compared to other compartments.
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, No. 2900, Hosur Road, Bangalore, Karnataka 560029, India.
G
G
Harish
Anita
A
Mahadevan
M M
MM
Srinivas Bharath
S K
SK
Shankar
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004396:Coloring Agents; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D019581:Neuropil / Q000201:enzymology / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000201:enzymology / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000201:enzymology / Q000378:metabolism*; D050050:Protein Carbonylation / Q000502:physiology; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D015415:Biomarkers; D004396:Coloring Agents; D009566:Nitrates; D016877:Oxidants; D013778:Tetrazolium Salts; D013844:Thiazoles; D008291:Malate Dehydrogenase; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; D005980:Glutathione Reductase; D002950:Citrate (si)-Synthase; D005982:Glutathione Transferase; C022616:thiazolyl blue; D005978:Glutathione