Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34

• Published in: PloS one 2016-03, Vol.11 (3), p.e0151026
• Main Authors: Shen, Yan, McMackin, Marissa Z, Shan, Yuxi, Raetz, Alan, David, Sheila, Cortopassi, Gino
• Format: Article
• Language: English
• Subjects: 8-Hydroxyguanine; Activation; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animal models; Animals; Ataxia; Behavior, Animal - drug effects; Biology and Life Sciences; Brain; Cell culture; Cell Line; Cellular proteins; Cerebellum; Cerebellum - drug effects; Cerebellum - metabolism; Cerebellum - pathology; Damage; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; DNA; DNA Damage; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA repair; Dorsal root ganglia; Enzymes; Female; Frataxin; Friedreich Ataxia - genetics; Friedreich Ataxia - metabolism; Friedreich's ataxia; Ganglia; Gene Expression; Gene Expression Regulation; Gene Knockdown Techniques; Genes; Genetic aspects; Health aspects; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - metabolism; Intracerebroventricular administration; Iron-Binding Proteins - genetics; Kinases; Lipopolysaccharides; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - adverse effects; Medicine and Health Sciences; Metabolites; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Mitochondrial DNA; Neurodegeneration; Neurosciences; Oxidative Stress; Phenanthrenes - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Properties; Protein deficiency; Proteins; Repair; Research and Analysis Methods; RNA, Small Interfering - genetics; Rodents; siRNA; Sulfur; Therapeutic applications
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151026

An inherited deficiency in the frataxin protein causes neurodegeneration of the dorsal root ganglia and Friedreich's ataxia (FA). Frataxin deficiency leads to oxidative stress and inflammatory changes in cell and animal models; however, the cause of the inflammatory changes, and especially what causes brain microglial activation is unclear. Here we investigated: 1) the mechanism by which frataxin deficiency activates microglia, 2) whether a brain-localized inflammatory stimulus provokes a greater microglial response in FA animal models, and 3) whether an anti-inflammatory treatment improves their condition. Intracerebroventricular administration of LPS induced higher amounts of microglial activation in the FA mouse model vs controls. We also observed an increase in oxidative damage in the form of 8-oxoguanine (8-oxo-G) and the DNA repair proteins MUTYH and PARP-1 in cerebellar microglia of FA mutant mice. We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1. Frataxin knockdown also induced a higher level of PARP-1 in MEF cells, and this was suppressed in MUTYH-/- knockout cells. Administration of the PARP-1 inhibitor PJ34 attenuated the microglial activation induced by intracerebroventricular injection of LPS. The combined administration of LPS and angiotensin II provoke an even stronger activation of microglia and neurobehavioral impairment. PJ34 treatment attenuated the neurobehavioral impairments in FA mice. These results suggest that the DNA repair proteins MUTYH and PARP-1 may form a pathway regulating microglial activation initiated by DNA damage, and inhibition of microglial PARP-1 induction could be an important therapeutic target in Friedreich's ataxia.