TY - JOUR
T1 - NF-κB in innate neuroprotection and age-related neurodegenerative diseases
AU - Lanzillotta, Annamaria
AU - Porrini, Vanessa
AU - Bellucci, Arianna
AU - Benarese, Marina
AU - Branca, Caterina
AU - Parrella, Edoardo
AU - Spano, Pier Franco
AU - Pizzi, Marina
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - BDNF
KW - C-Rel deficient mice
KW - Epigenetic drugs
KW - NF-κB
KW - RelA (K310)
UR - http://www.scopus.com/inward/record.url?scp=84930664415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930664415&partnerID=8YFLogxK
U2 - 10.3389/fneur.2015.00098
DO - 10.3389/fneur.2015.00098
M3 - Article
AN - SCOPUS:84930664415
VL - 6
JO - Frontiers in Neurology
JF - Frontiers in Neurology
SN - 1664-2295
IS - MAY
M1 - 00098
ER -