FK506 ameliorates cell death features in Huntington's disease striatal cell models

Tatiana R. Rosenstock, Olga Martins de Brito, Vitoria Lombardi, Susana Ribeiro dos Louros, Marcio Ribeiro, Sandra Almeida, Ildete Luisa Ferreira, Catarina R. Oliveira, A. Cristina Rego*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 0.3 mM 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 10 nM 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. (C) 2011 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)600-609
Number of pages10
JournalNeurochemistry International
Issue number5
Publication statusPublished - Oct 2011

Keywords / Materials (for Non-textual outputs)

  • 3-Nitropropionic acid
  • Cell death
  • FK506
  • Mutant huntingtin
  • Mitochondrial dysfunction
  • Striatal neurons
  • RAT


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