title: Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion.
abstract: Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. Likewise, activation of glycogen synthase kinase-3 (GSK-3) has been proposed to play an important role in neurodegeneration. This multifunctional protein kinase is involved in a number of cellular functions and we previously showed that chronic inhibition of GSK-3 protects neuronal cells against mitochondrial dysfunction-elicited cell death, through a mechanism involving increased glucose metabolism and the translocation of hexokinase II (HKII) to mitochondria. Here, we sought to gain deeper insight into the molecular basis of this neuroprotection. We found that chronic inhibition of GSK-3, either genetically or pharmacologically, elicited a marked increase in brain-derived neurotrophic factor (BDNF) secretion, which in turn conferred resistance to mitochondrial dysfunction through subcellular re-distribution of HKII. These results define a molecular pathway through which chronic inhibition of GSK-3 may protect neuronal cells from death. Moreover, they highlight the potential benefits of enhanced neurotrophic factor secretion as a therapeutic approach to treat neurodegenerative diseases.
authors.affiliation: Dept. de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC) Universidad Autónoma de Madrid, 28049 Madrid, Spain. Alfredo_gimenez-cassina@dfci.harvard.edu
authors.forename: Alfredo
authors.initials: A
authors.lastname: Giménez-Cassina
authors.forename: Filip
authors.initials: F
authors.lastname: Lim
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Nido
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology*; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D014475:Uncoupling Agents; D012402:Rotenone; D006593:Hexokinase; D038362:Glycogen Synthase Kinase 3