title: Apoptosis signal-regulating kinase-1 aggravates ROS-mediated striatal degeneration in 3-nitropropionic acid-infused mice.
abstract: Apoptosis signal-regulating kinase-1 (ASK1), an early signaling element in the cell death pathway, has been suggested to participate in the pathology of neurodegenerative diseases, which may be associated with environmental factors that impact the diseases. Although it is not entirely elucidated, 3-nitropropionic acid (3-NP) provokes mitochondrial dysfunction and selectively forms striatal lesions similar to those found in Huntington's disease. The current study investigated whether ASK1 is involved in striatal pathology following chronic systemic infusion of 3-NP. The results show that ASK1 acts as a primary mediator of there active oxygen species (ROS) cell death signal cascade in the 3-NP-damaged striatal region by disrupting the positive feedback cycle. In 3-NP-infused striatal lesions, ROS increased ASK1. Superoxide dismutase transgenic (SOD-tg) mice reduced ASK1by scavenging ROS, and reduction of ASK1leads to a reduction in cell death. However, ASK1 down-regulation in 3-NP infusion mice also decreased striatal cell death without scavenging ROS. In contrast decreasing cell death by si-ASK1 treatment along with 3-NP in both SOD tg and wild-type mice (wt), cell death rebounded when ASK1 peptide was added to SOD tg mice. The present study suggests that ROS-inducing ASK1 may be an important step in the pathogenesis of 3-NP infused striatal lesions in murine brains.
authors.affiliation: Department of Neurology, College of Medicine, Yonsei University, Republic of Korea; Department of Anatomy and Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Kyoung Joo
authors.initials: KJ
authors.lastname: Cho
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Cheon
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Gyung Whan
authors.initials: GW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D009574:Nitro Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Apoptosis signal-regulating kinase 1; Superoxide dismutase; siRNA