Related Experiment Video
Updated: May 31, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
FK506 ameliorates cell death features in Huntington's disease striatal cell models
Tatiana R Rosenstock1, Olga Martins de Brito, Vitoria Lombardi
1Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Insights
FK506, a calcineurin inhibitor, shows neuroprotective effects in Huntington
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a genetic neurodegenerative disorder.
- Striatal neurodegeneration and apoptosis are key features of HD.
- FK506 (calcineurin inhibitor) has demonstrated neuroprotective potential in HD models.
Purpose of the Study:
- To investigate the neuroprotective effects of FK506 in striatal cells relevant to Huntington's disease.
- To evaluate FK506's impact on apoptosis and necrosis under various stress conditions.
Main Methods:
- Primary rat striatal neurons treated with 3-nitropropionic acid (3-NP).
- Immortalized striatal STHdh cells (normal and HD mutant) exposed to 3-NP or staurosporine (STS).
- Assessment of caspase-3 activation, DNA fragmentation, necrosis, and mitochondrial factors.
Main Results:
- FK506 inhibited 3-NP-induced apoptosis and necrosis in rat neurons.
- In HD mutant cells, FK506 partially reverted caspase-3 activation but did not significantly affect mitochondrial factors under basal conditions.
- FK506 prevented cell death from apoptosis and moderate necrosis in HD mutant cells exposed to low-dose STS.
Conclusions:
- FK506 demonstrates neuroprotective capabilities against apoptosis and necrosis in Huntington's disease models.
- The efficacy of FK506 may depend on the severity of the cell death stimulus.
- FK506 holds potential for therapeutic intervention in Huntington's disease, particularly under milder pathological conditions.
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.
