Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders.
Excessive release of proinflammatory products by activated glia causes neurotoxicity and participates in the pathogenesis of neurodegenerative disorders. Recently, poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to play a key role in nuclear factor kappa B (NF-kappaB)-driven expression of inflammatory mediators by glia during the neuroimmune response. Here we report the novel finding that the enzymatic activity of PARP-1 promotes, in an beta-nicotinamide adenine dinucleotide-dependent fashion, the DNA binding of NF-kappaB in microglia exposed to lipopolysaccharides, interferon-gamma or beta-amyloid 1-40. Consistently, we found that targeting NF-kappaB-dependent glial activation with pharmacological inhibitors of PARP-1 enzymatic activity reduces expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin 1beta, tumor necrosis factor alpha and amyloid precursor protein, and reduces the neurotoxic potential of activated glia in vitro. Importantly, pharmacological inhibition of lipopolysaccharide-induced poly(ADP-ribose) formation in vivo suppresses neuroinflammation and related neural cell death. Our findings build on prior published reports in PARP-1 null mice and highlight the importance of PARP-1 enzymatic activity in transcriptional control during glial activation, identifying PARP-1 activity-dependent regulation of NF-kappaB as a novel pharmacological target for therapeutic intervention in the treatment of acute and chronic neurodegenerative disorders.
Chiarugi
Alberto
A
Department of Neuroscience, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachussets, USA. alberto_chiarugi@hotmail.com
Moskowitz
Michael A
MA
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D016328:NF-kappa B / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000502:physiology*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases