title: FK506 ameliorates cell death features in Huntington's disease striatal cell models.
abstract: Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh(7/7)) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh(111/111)), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh(111/111) cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh(111/111) cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh(111/111) cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt.
authors.affiliation: Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Tatiana R
authors.initials: TR
authors.lastname: Rosenstock
authors.forename: Olga Martins
authors.initials: OM
authors.lastname: de Brito
authors.forename: Vitoria
authors.initials: V
authors.lastname: Lombardi
authors.forename: Susana
authors.initials: S
authors.lastname: Louros
authors.forename: Marcio
authors.initials: M
authors.lastname: Ribeiro
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.forename: Ildete Luisa
authors.initials: IL
authors.lastname: Ferreira
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D009574:Nitro Compounds / Q000633:toxicity; D009687:Nuclear Proteins / Q000235:genetics; D011422:Propionates / Q000633:toxicity; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D009687:Nuclear Proteins; D011422:Propionates; D053148:Caspase 3; D019311:Staurosporine; C015392:3-nitropropionic acid; D016559:Tacrolimus