title: Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry.
abstract: Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg, Fribourg, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Marathe
authors.affiliation: Receptor Biology Section, NINDS/NIH, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg, Fribourg, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Brai
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg, Fribourg, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Kaczarowski
authors.affiliation: Department of Medicine, Institute of Anatomy, University of Fribourg, Fribourg, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Alberi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051880:Receptors, Notch; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D007608:Kainic Acid
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