title: Hsp90 activity is necessary to acquire a proper neuronal polarization.
abstract: Chaperones are critical for the folding and regulation of a wide array of cellular proteins. Heat Shock Proteins (Hsps) are the most representative group of chaperones. Hsp90 represents up to 1-2% of soluble protein. Although the Hsp90 role is being studied in neurodegenerative diseases, its role in neuronal differentiation remains mostly unknown. Since neuronal polarity mechanisms depend on local stability and degradation, we asked whether Hsp90 could be a regulator of axonal polarity and growth. Thus, we studied the role of Hsp90 activity in a well established model of cultured hippocampal neurons using an Hsp90 specific inhibitor, 17-AAG. Our present data shows that Hsp90 inhibition at different developmental stages disturbs neuronal polarity formation or axonal elongation. Hsp90 inhibition during the first 3h in culture promotes multiple axon morphology, while this inhibition after 3h slows down axonal elongation. Hsp90 inhibition was accompanied by decreased Akt and GSK3 expression, as well as, a reduced Akt activity. In parallel, we detected an alteration of kinesin-1 subcellular distribution. Moreover, these effects were seconded by changes in Hsp70/Hsc70 subcellular localization that seem to compensate the lack of Hsp90 activity. In conclusion, our data strongly suggests that Hsp90 activity is necessary to control the expression, activity or location of specific kinases and motor proteins during the axon specification and axon elongation processes. Even more, our data demonstrate the existence of a "time-window" for axon specification in this model of cultured neurons after which the inhibition of Hsp90 only affects axonal elongation mechanisms.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Univ. Autonoma de Madrid, 28049 Madrid, Spain; Dpto Química Física Aplicada, Univ. Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Benitez
authors.affiliation: Instituto Cajal, CSIC, Department of Molecular, Cellular and Developmental Neurobiology, Madrid 28002, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Sanchez-Ponce
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Cajal, CSIC, Department of Molecular, Cellular and Developmental Neurobiology, Madrid 28002, Spain. Electronic address: jjgarrido@cajal.csic.es.
authors.forename: J J
authors.initials: JJ
authors.lastname: Garrido
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, Univ. Autonoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: fwandosell@cbm.uam.es.
authors.forename: F
authors.initials: F
authors.lastname: Wandosell
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D016764:Cell Polarity / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D016547:Kinesins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins
keywords: Axon; Hsp90; Neuronal chaperons; Neuronal polarity; PI3K–Akt pathway