title: Tau pathology-mediated presynaptic dysfunction.
abstract: Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases.
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Departments of Neurology and Physiology/Pharmacology, Brooklyn, NY 11203, United States; Marine Biological Laboratory, Woods Hole, MA 02543, United States. Electronic address: Herman.Moreno@downstate.edu.
authors.forename: H
authors.initials: H
authors.lastname: Moreno
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors.forename: G
authors.initials: G
authors.lastname: Morfini
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Departments of Neurology and Physiology/Pharmacology, Brooklyn, NY 11203, United States; Marine Biological Laboratory, Woods Hole, MA 02543, United States.
authors.forename: L
authors.initials: L
authors.lastname: Buitrago
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States.
authors.forename: G
authors.initials: G
authors.lastname: Ujlaki
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, United States.
authors.forename: S
authors.initials: S
authors.lastname: Choi
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, United States.
authors.forename: E
authors.initials: E
authors.lastname: Yu
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Pathology and Forensic Medicine, Riberão Preto School of Medicine, University of São Paulo, Ribeirão Preto, SP 14000-000, Brazil.
authors.forename: J E
authors.initials: JE
authors.lastname: Moreira
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Avila
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors.forename: S T
authors.initials: ST
authors.lastname: Brady
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD 20824, United States.
authors.forename: H
authors.initials: H
authors.lastname: Pant
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, United States.
authors.forename: M
authors.initials: M
authors.lastname: Sugimori
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA 02543, United States; Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, United States. Electronic address: Rodolfo.Llinas@nyumc.org.
authors.forename: R R
authors.initials: RR
authors.lastname: Llinás
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D049832:Decapodiformes; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D016875:tau Proteins / Q000633:toxicity*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C054369:MAPT protein, human; D019837:Ryanodine Receptor Calcium Release Channel; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D002118:Calcium
keywords: Cdk5; GSK3; IP3 receptor; phosphatase-activating domain of tau; ryanodine receptor; tauopathy