title: Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate.
abstract: Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Weifang Medical University, Weifang 261000, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: H-Z
authors.initials: HZ
authors.lastname: Jiang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: H-Q
authors.initials: HQ
authors.lastname: Jiang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: X-D
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: G-T
authors.initials: GT
authors.lastname: Dong
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: T-H
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China. Electronic address: fenghonglin186@sina.com.
authors.forename: H-L
authors.initials: HL
authors.lastname: Feng
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018021:Lithium Chloride / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D014162:Transfection; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D014635:Valproic Acid; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D018021:Lithium Chloride
keywords: ALS; Notch signaling pathway; VPA; lithium