title: Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Marissa Z
authors.initials: MZ
authors.lastname: McMackin
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of Chemistry, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Raetz
authors.affiliation: Department of Chemistry, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Sheila
authors.initials: S
authors.lastname: David
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, California, 95616, United States of America.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000096923:Frataxin
chemical_list: D000804:Angiotensin II; D045647:DNA Glycosylases; D033862:Iron-Binding Proteins; D008070:Lipopolysaccharides; D010616:Phenanthrenes; D011065:Poly(ADP-ribose) Polymerases; D034741:RNA, Small Interfering; D000096923:Frataxin; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C061738:mutY adenine glycosylase