NF-κB unbalance and dysfunction in acute and age-related neurodegenerative disease

The mechanisms underlying the progressive loss of neurons in age-related neurodegenerative diseases remain unknown to date. NF-κB factors are cardinal transcriptional regulators of inflammation and apoptosis and have been involved in the brain programming of systemic aging as well as in the pathogenesis of brain ischemia. Studies focusing on the complexity of NF-κB transcriptional activity in neuronal cell death showed that the composition of NF-κB active dimers and epigenetic mechanisms modulating histone acetylation finely condition neuronal vulnerability to brain ischemia. The atypical activation of NF-κB RelA acetylated on lysine 310 (K310) residue can trigger the expression of apoptotic genes but also constitutes a target for a neuroprotective combination of epigenetic drugs. Conversely, activation of NF-κB/c-Rel promotes neuroprotective effects through the transcription of specific anti-apoptotic genes. In addition, the absence of c-Rel shatters the resilience of nigral dopaminergic (DA) neurons to aging and induces parkinsonian features in mice. Indeed, we found that c-Rel-deficient mice show an increased RelA activation in the basal ganglia, and develop an L-DOPA-responsive parkinsonism associated with loss of DA neurons in the substantia nigra, neuroinflammation, accumulation of alpha-synuclein and iron during aging. Here, we discuss the effect of unbalanced activation of RelA and c-Rel during aging and propose novel challenges for the development of potential therapeutic strategies for neurodegenerative diseases.