title: NF-κB in Innate Neuroprotection and Age-Related Neurodegenerative Diseases.
abstract: NF-κB factors are cardinal transcriptional regulators of inflammation and apoptosis, involved in the brain programing of systemic aging and in brain damage. The composition of NF-κB active dimers and epigenetic mechanisms modulating histone acetylation, finely condition neuronal resilience to brain insults. In stroke models, the activation of NF-κB/c-Rel promotes neuroprotective effects by transcription of specific anti-apoptotic genes. Conversely, aberrant activation of NF-κB/RelA showing reduced level of total acetylation, but site-specific acetylation on lysine 310, triggers the expression of pro-apoptotic genes. Constitutive knockout of c-Rel shatters the resilience of substantia nigra (SN) dopaminergic (DA) neurons to aging and induces a parkinsonian like pathology in mice. c-rel(-/-) mice show increased level of aberrantly acetylated RelA in the basal ganglia, neuroinflammation, accumulation of alpha-synuclein, and iron. Moreover, they develop motor deficits responsive to l-DOPA treatment and associated with loss of DA neurons in the SN. Here, we discuss the effect of unbalanced activation of RelA and c-Rel during aging and propose novel challenges for the development of therapeutic strategies in neurodegenerative diseases.
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lanzillotta
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy ; IRCCS, San Camillo Hospital , Venice , Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Porrini
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bellucci
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Benarese
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Parrella
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy ; IRCCS, San Camillo Hospital , Venice , Italy.
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Spano
authors.affiliation: Department of Molecular and Translational Medicine, National Institute of Neuroscience, University of Brescia , Brescia , Italy ; IRCCS, San Camillo Hospital , Venice , Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Pizzi
keywords: BDNF; NF-κB; RelA (K310); c-Rel deficient mice; epigenetic drugs