title: The neuroregenerative mechanism mediated by the Hsp90-binding immunophilin FKBP52 resembles the early steps of neuronal differentiation.
abstract: BACKGROUND AND PURPOSE The immunosuppressive macrolide FK506 (tacrolimus) shows neuroregenerative action by a mechanism that appears to involve the Hsp90-binding immunophilin FKBP52. This study analyses some aspects of the early steps of neuronal differentiation and neuroregeneration. EXPERIMENTAL APPROACH Undifferentiated murine neuroblastoma cells and hippocampal neurones isolated from embryonic day-17 rat embryos were induced to differentiate with FK506. Subcellular relocalization of FKBP52, Hsp90 and its co-chaperone p23 was analysed by indirect immunofluorescence confocal microscopy and by Western blots of axonal fractions isolated from cells grown on a porous transwell cell culture chamber. Neuroregeneration was evaluated using a scratch-wound assay. KEY RESULTS In undifferentiated cells, FKBP52, Hsp90 and p23 are located in the cell nucleus, forming an annular structure that disassembles when the differentiation process is triggered by FK506. This was observed in the N2a cell line and in hippocampal neurones. More importantly, the annular structure of chaperones is reassembled after damaging the neurones, whereas FK506 prompts their rapid regeneration, a process linked to the subcellular redistribution of the heterocomplex. CONCLUSIONS AND IMPLICATIONS There is a direct relationship between the disassembly of the chaperone complex and the progression of neuronal differentiation upon stimulation with the immunophilin ligand FK506. Both neuronal differentiation and neuroregeneration appear to be mechanistically linked, so the elucidation of one mechanism may lead to unravel the properties of the other. This study also implies that the discovery of FK506 derivatives, devoid of immunosuppressive action, would be therapeutically significant for neurotrophic use.
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET and Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: H R
authors.initials: HR
authors.lastname: Quintá
authors.forename: M D
authors.initials: MD
authors.lastname: Galigniana
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D016559:Tacrolimus
references.citation: J Neurosci. 2009 May 20;29(20):6625-34
references.pmid: 19458233
references.citation: J Neurosci. 2007 Jan 17;27(3):507-16
references.pmid: 17234583
references.citation: J Neurosci. 1987 Nov;7(11):3723-35
references.pmid: 3119792
references.citation: FASEB J. 2007 Sep;21(11):2787-97
references.pmid: 17435176
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6270-4
references.pmid: 1631118
references.citation: Curr Biol. 2008 Jul 8;18(13):992-1000
references.pmid: 18595703
references.citation: Stem Cells. 2008 Oct;26(10):2467-74
references.pmid: 18635867
references.citation: J Biol Chem. 2003 Sep 12;278(37):34764-73
references.pmid: 12807878
references.citation: J Neurochem. 2010 Nov;115(3):716-34
references.pmid: 20796173
references.citation: Ther Drug Monit. 2009 Apr;31(2):139-52
references.pmid: 19177031
references.citation: Mol Cell Biol. 2010 Mar;30(5):1285-98
references.pmid: 20038533
references.citation: Biochemistry. 1992 Apr 28;31(16):3896-901
references.pmid: 1373650
references.citation: Transplant Proc. 2004 Mar;36(2 Suppl):25S-32S
references.pmid: 15041303
references.citation: Cell Signal. 2004 Aug;16(8):857-72
references.pmid: 15157665
references.citation: Mol Cell Biol. 2009 Sep;29(17):4788-97
references.pmid: 19581287
references.citation: J Pharmacol Exp Ther. 1999 Jun;289(3):1202-10
references.pmid: 10336507
references.citation: Int J Biochem Cell Biol. 2005 Jan;37(1):42-7
references.pmid: 15381148
references.citation: Curr Opin Pharmacol. 2011 Aug;11(4):314-9
references.pmid: 21511531
references.citation: Biochemistry. 2007 Dec 11;46(49):14044-57
references.pmid: 18001136
references.citation: Biochemistry. 2002 Nov 19;41(46):13602-10
references.pmid: 12427021
references.citation: Nature. 2002 Feb 28;415(6875):1035-8
references.pmid: 11875572
references.citation: Biochemistry. 2000 Nov 21;39(46):14314-21
references.pmid: 11087380
references.citation: Nucleus. 2010 Jul-Aug;1(4):299-308
references.pmid: 21113270
references.citation: EMBO Rep. 2007 Oct;8(10):914-9
references.pmid: 17906672
references.citation: Br J Pharmacol. 2003 Nov;140(5):825-9
references.pmid: 14559856
references.citation: J Cell Biol. 1980 Jun;85(3):890-902
references.pmid: 6248568
references.citation: Proteomics. 2007 Mar;7(6):910-20
references.pmid: 17370269
references.citation: Mol Endocrinol. 2002 Sep;16(9):1987-98
references.pmid: 12198236
references.citation: J Cell Sci. 2006 May 15;119(Pt 10):2065-72
references.pmid: 16638804
references.citation: Biochemistry. 2005 Feb 15;44(6):2030-8
references.pmid: 15697228
references.citation: Neurosignals. 2004 May-Jun;13(3):122-9
references.pmid: 15067199
references.citation: Exp Cell Res. 2006 Jan 15;312(2):198-204
references.pmid: 16289154
references.citation: Cell Stress Chaperones. 2003 Summer;8(2):108-13
references.pmid: 14627195
references.citation: Mol Endocrinol. 2007 Dec;21(12):2956-67
references.pmid: 17717070
references.citation: Curr Top Med Chem. 2003;3(12):1368-75
references.pmid: 12871168
references.citation: J Antibiot (Tokyo). 1987 Sep;40(9):1249-55
references.pmid: 2445721
references.citation: Eur J Cell Biol. 1996 Aug;70(4):322-30
references.pmid: 8864660
references.citation: J Neurosci. 2010 Nov 17;30(46):15374-82
references.pmid: 21084594
references.citation: Prog Transplant. 2009 Sep;19(3):277-84
references.pmid: 19813492
references.citation: J Cell Sci. 2008 Jan 15;121(Pt 2):178-85
references.pmid: 18187450