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

The mechanisms underlying the progressive loss of neurons in age-related neurodegenerative diseasesremain unknown to date. NF-κB factors are cardinal transcriptional regulators of inflammation andapoptosis and have been involved in the brain programming of systemic aging as well as in the pathogenesisof brain ischemia. Studies focusing on the complexity of NF-κB transcriptional activity in neuronal celldeath showed that the composition of NF-κB active dimers and epigenetic mechanisms modulatinghistone acetylation finely condition neuronal vulnerability to brain ischemia. The atypical activation ofNF-κB RelA acetylated on lysine 310 (K310) residue can trigger the expression of apoptotic genes butalso constitutes a target for a neuroprotective combination of epigenetic drugs. Conversely, activation ofNF-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 andinduces parkinsonian features in mice. Indeed, we found that c-Rel-deficient mice show an increased RelAactivation in the basal ganglia, and develop an L-DOPA-responsive parkinsonism associated with loss ofDA neurons in the substantia nigra, neuroinflammation, accumulation of alpha-synuclein and iron duringaging. Here, we discuss the effect of unbalanced activation of RelA and c-Rel during aging and proposenovel challenges for the development of potential therapeutic strategies for neurodegenerative diseases.