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1

The effect of tetrahydrocarbozoles on the ER calcium release and SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease

100%
Maciag F., Czeredys M., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
|
nr Supl.
BACKGROUND AND AIMS: Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an extended polyglutamine tail in the huntingtin (HTT) protein and manifesting itself by neurodegeneration of medium spiny neurons (MSN) in the striatum. An early event in the pathology of HD is deregulated Ca2+ homeostasis (Giacomello et al. 2013). One of the mechanisms that regulate Ca2+ homeostasis is store-operated Ca2+ entry (SOCE), which was shown to be enhanced in HD (Wu et al. 2011). However, the mechanism by which mutated HTT affects SOCE is still unknown and there is no effective treatment of HD. RESULTS: Therefore, we assessed the alterations of the Ca2+ signalosome in the striatum of transgenic YAC128 mice, a model of HD (Czeredys et al. 2013). In MSN isolated from these mice we detected an about 10% increase in the basal Ca2+ level. We found that the activity of SOCE was enhanced about 30%. Since the deregulation of Ca2+ homeostasis and signaling is considered to be the primary event in HD, the aim of this work was to investigate the effect of compounds called tetrahydrocarbazoles on the ER Ca2+ release induced by mGluR1/5 receptor agonist, DHPG (3,5-dihydroxyglycine), as well as their influence on SOCE in MSN from YAC128 mice. It was previously shown that tetrahydrocarbazoles stabilize the ER Ca2+ release induced by carbachole in HEK293 cells overexpressing mutated presenilin 1, a cellular Alzheimer’s disease model (Honarnejad et al. 2014). We have confirmed by immunostaining that in our in vitro model of HD, MSN culture from YAC128 mice, mGluR1/5 receptors are specifically expressed. The MSN cells were treated with chosen tetrahydrocarbazoles and Ca2+ was imaged with Fura-2 AM. CONCLUSIONS: Our preliminary data suggest that some tested compounds have a stabilizing effect on Ca2+ level in HD cellular model. Tetrahydrocarbazoles could be potentially used as drugs stabilizing the disturbed Ca2+ homeostasis in Huntington’s disease.
2

Investigation of Ca2plus homeostasis and behavioral changes in transgenic mice overexpressing key store-operated calcium entry proteins

100%
Maciag F., Majewski L., Boguszewski P. M., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: Store-operated calcium entry (SOCE) is the major Ca2+ influx pathway in non-excitable cells. However, recent studies suggest its important roles in neurons. In SOCE, the depletion of Ca2+ from the endoplasmic reticulum (ER) causes an influx of Ca2+ from the extracellular space to refill the intracellular Ca2+ stores. STIMs are Ca2+ ER sensors that mediate SOCE by interacting with the ion channels in the cell membrane – ORAIs. Using transgenic mice with neuronal overexpression of STIMs and/or ORAIs, we investigate their role in neural function. Recently, we showed electrophysiological changes in hippocampi from female mice overexpressing ORAI1. Earlier studies from our group revealed increased cytoplasmic Ca2+ levels in cultured neurons overexpressing both ORAI1 and STIM2. Currently, we are extending these studies with the use of double transgenic STIM2/ORAI1 mice. AIM(S): To investigate the role of SOCE proteins in neurons, and the effect of STIM2 and ORAI1 overexpression on Ca2+ homeostasis, synaptic functions, and behavior. METHOD(S): We use transgenic mice that overexpress STIM and/or ORAI proteins in brain neurons. For studying Ca2+ homeostasis, we stain hippocampal slices with Fura‑2 AM probe. To assess locomotor functions and cognitive abilities of these mice, behavioral tests are utilized. Synaptic transmission and plasticity phenomena are investigated by electrophysiological recordings from hippocampal slices. RESULTS: We have recently observed spontaneous seizure-like events in aged female mice overexpressing ORAI1. These observations correlated with changes in the response of hippocampal slices to pro-epileptic drugs. Currently, we are focusing our analyses on the double transgenic STIM2/ORAI1 mouse line. CONCLUSIONS: Our previous data support the view that SOCE proteins play an important role in neurons. Currently, we aim to elucidate the involvement of STIM2 and ORAI1 proteins in neural function. FINANCIAL SUPPORT: Maestro to JK from NCN (2011/02/A/NZ3/00144).
3

Role of Huntingtin-associated protein 1 in the regulation of SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease

76%
Czeredys M., Maciag F., Vigont V., Kaznacheyeva E., Methner A., Kuznicki J.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein and characterized by deregulated Ca2+ homeostasis (Giacomello et al. 2013). One of the mechanisms that regulate Ca2+ homeostasis is store-operated Ca2+ entry (SOCE) (Majewski and Kuźnicki 2015), which is enhanced in HD (Wu et al. 2011). The mechanism by which mutated HTT affects SOCE is unknown. The changes in Ca2+ homeostasis could be explained by increased expression of huntingtin-associated protein 1 (Hap1) mRNA (3-fold) and HAP1 protein (about 2-fold) in the striatum of YAC128 mice, which we detected (Czeredys et al. 2013). If HAP1 influences ER Ca2+ release mediated by IP3R in MSN from YAC128 mice, which was shown in other HD models by Tang et al. (2003, 2004), its increased level may explain changes in SOCE described by Wu et al. (2011). The aim of this study is to determine the role of HAP1 protein in the regulation of SOCE in MSN from transgenic mice YAC128, an HD model. METHODS: Using prepared lentiviral constructs we overexpressed HAP1a or HAP1b in YAC128 neurons, and in HEK293 cells overexpressing mutant HTT. We imaged cells with Fura-2AM, a selective fluorescent Ca2+ probe. SOCE was measured after depletion of intracellular Ca2+ by mGluR1/5 receptor agonist, DHPG (3,5- dihydroxyglycine) and subsequent incubation of cells in 2 mM Ca2+ media. RESULTS: In HD MSN we detected about 10% increase in basal Ca2+ level and found that the activity of SOCE was enhanced about 30%, thereby confirming results of Wu et al. (2011). The preliminary results showed that overexpressed Hap1 protein is involved in SOCE pathway in studied cells. Using electrophysiology we will also determine changes in the SOC currents in MSN and SK-N-SH cells, both transduced with HAP1 and mutant HTT. CONCLUSION: The investigation of the role of HAP1 protein in deregulated.
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