Differential regulation of Mn-superoxide dismutase in neurons and astroglia by HIV-1 gp120: Implications for HIV-associated dementia.
HIV-associated dementia, like several other neurodegenerative diseases, is characterized by selective degeneration of neurons amidst survival of glial cells like astroglia. The molecular basis of such selective susceptibility within the same milieu remains largely unknown. Neurons are rarely infected by the virus. However, they are vulnerable to viral products, like HIV-1 coat protein gp120. Interestingly, gp120 induced oxidative stress in neurons, but not in astroglia. This led us to postulate that astroglia were armed with a more efficient antioxidant system than neurons. Here, we report that the constitutive level of MnSOD (SOD2), the major cellular antioxidant enzyme, is significantly higher in astroglia than in neurons. Furthermore, gp120 treatment enhanced MnSOD levels in astroglia but decreased the same in neurons. This increase in astroglial MnSOD was dependent on NF-kappaB, the crucial transcription factor required for sod2 gene transcription. Blocking NF-kappaB with p65-antisense, p65-si-RNA, or a specific inhibitor, NBD peptide, led to reduced MnSOD levels and enhanced vulnerability of astroglia to gp120. Additionally, neurons were found to have a lower constitutive level of NF-kappaB p65 than astrocytes. Overexpression of p65 increased the level of MnSOD in neurons. This, in turn, elicited greater neuronal resistance to gp120. Taken together, our study suggests that astroglia manifest a higher threshold for gp120-induced lethality than neurons due to greater MnSOD availability, which is demonstrated due to greater level of NF-kappaB p65.
Saha
Ramendra N
RN
Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center College of Dentistry, 40th and Holdrege Street, Lincoln, NE 68583, USA.
Pahan
Kalipada
K
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000196:embryology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; D034741:RNA, Small Interfering; D013481:Superoxides; D013482:Superoxide Dismutase