Neuroprotective role for the p50 subunit of NF-kappa B 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 n eurons in response to excitotoxic, metabolic, and oxidative stress. Cell-cu lture data suggest that activation of NF-kappaB can prevent neuronal apopto sis, but its role in vivo is unclear and the specific kappaB subunits invol ved are unknown. In Huntington's disease (HD), striatal neurons degenerate, and a similar pattern of neuronal vulnerability occurs in rats and mice fo llowing exposure to the mitochondrial toxin 3-nitropropionic acid (3NP). We report that mice lacking the p50 subunit of NF-kappaB exhibit increased da mage to striatal neurons following administration of 3NP. The neuronal deat h occurs by apoptosis as indicated by increased caspase activation and DNA fragmentation into oligonucleosomes. NF-kappaB activity is markedly increas ed 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 majo rity of 3NP-induced NF-kappaB DNA-binding activity in striatum. Cultured st riatal neurons from p50-/- mice exhibited enhanced oxidative stress, pertur bed calcium regulation, and increased cell death following exposure to 3NP, suggesting a direct adverse effect of p50 deficiency in striatal neurons.