title: Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice.
abstract: α-Synuclein is a key pathogenic protein in α-synucleinopathies including Parkinson's disease, and its overexpression and aggregation in model systems are associated with a neuroinflammatory response and increased oxidative stress. Apoptosis signal-regulating kinase 1 (ASK1) is activated upon stress signaling events such as oxidative stress and is a central player linking oxidative stress with neuroinflammation. Here, we demonstrate that overexpression of human α-synuclein activates ASK1 in both PC12 cells and in the brains of α-synuclein transgenic mice. Deleting ASK1 in mice mitigates the neuronal damage and neuroinflammation induced by α-synuclein and improves performance of the animals on the rotarod. ASK1 deletion does not impact the aggregation profile or phosphorylation state of α-synuclein in the mouse brain. These results collectively implicate ASK1 in the cascade of events triggered by α-synuclein overexpression, likely because of the inflammatory response and oxidative stress that lead to ASK1 activation. These conclusions raise the possibility that potent antioxidants and anti-inflammatory agents may ameliorate the phenotype of α-synucleinopathies.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Woo
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Im
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Eun S
authors.initials: ES
authors.lastname: Park
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: He
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, NJ, USA. Electronic address: m.mouradian@rutgers.edu.
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism / Q000502:physiology*; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000235:genetics; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein; D048848:MAP Kinase Kinase Kinase 5
keywords: Alpha-synuclein; Neurodegeneration; Neuroinflammation; Neuroprotection; Oxidative stress; Parkinson's disease