Neuroprotective role for the p50 subunit of NF-kappaB in an experimental model of Huntington's disease.
Prototypical NF-kappaB consists of a transcription factor dimer of p50 and p65, and an inhibitory subunit called I-kappaB. NF-kappaB is activated in neurons in response to excitotoxic, metabolic, and oxidative stress. Cell-culture data suggest that activation of NF-kappaB can prevent neuronal apoptosis, but its role in vivo is unclear and the specific kappaB subunits involved are unknown. In Huntington's disease (HD), striatal neurons degenerate, and a similar pattern of neuronal vulnerability occurs in rats and mice following exposure to the mitochondrial toxin 3-nitropropionic acid (3NP). We report that mice lacking the p50 subunit of NF-kappaB exhibit increased damage to striatal neurons following administration of 3NP. The neuronal death occurs by apoptosis as indicated by increased caspase activation and DNA fragmentation into oligonucleosomes. NF-kappaB activity is markedly increased in striatum 24-72 h following 3NP administration in wild-type mice, but not in mice lacking p50, indicating that p50 is necessary for the vast majority of 3NP-induced NF-kappaB DNA-binding activity in striatum. Cultured striatal neurons from p50-/- mice exhibited enhanced oxidative stress, perturbed calcium regulation, and increased cell death following exposure to 3NP, suggesting a direct adverse effect of p50 deficiency in striatal neurons.
Yu
Z
Z
Sanders-Brown Research Center on Aging, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA.
Zhou
D
D
Cheng
G
G
Mattson
M P
MP
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006816:Huntington Disease / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000494:pharmacology
D003292:Convulsants; D016328:NF-kappa B; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D002118:Calcium