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1

Transgenic mice with dysregulated Ca2plus homeostasis in neurons as a model of age-induced neurodegeneration

100%
Majewski L., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
|
nr Suppl.1
Altered Ca2+ homeostasis has recently emerged as one of the early events responsible for Alzheimer’s disease (AD). Disturbances in Ca2+ signaling are found before any obvious extracellular Aβ pathology in patients with sporadic AD and it has been shown frequently, that Ca2+ dysfunction augments Aβ formation and Tau hyperphosphorylation. It is suggested, that brain ageing is a result of a subtle, but long-lasting dysregulation of Ca2+ homeostasis in neurons, which may explain that age is the major risk factor in AD. Our group showed that the intracellular Ca2+ level in resting neurons can be modulated by overexpression of STIM proteins. These proteins sense calcium level in ER and are involved in the Store Operated Calcium Entry (SOCE). The objective of our project is to understand how elevated basal Ca2+ level in neurons contributes to neurodegeneration. To achieve this goal constructs for STIM proteins and ORAI1 Ca2+ channels were created and procedures of transgenesis were completed to generate transgenic mice. The animals are now being tested for the transgenes. We will next analyze Ca2+ homeostasis in neurons of the transgenic mice. If they have expected phenotype, other properties will be monitored including behavior and susceptibility to neurodegeneration.
2

O rolnictwie i ekologii slow kilka

99%
Majewski L.
Zdrowa Żywność - Zdrowy Styl Życia
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1992
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nr 3
8-9
3

Miozyny w jądrze komórkowym

81%
Sobczak M., Majewski L., Redowicz M. J.
Postępy Biochemii
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2009
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tom 55
|
nr 2
4

Myosin VI is associated with secretory granules and is present in the nucleus in adrenal medulla chromaffin cells

81%
Majewski L., Sobczak M., Redowicz M. J.
Acta Biochimica Polonica
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2010
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tom 57
|
nr 1
109-114
Myosin VI (MVI) is the only known myosin walking towards minus end of actin filaments. Here, MVI, but not myosins IB or IIB, was detected in chromaffin granules isolated from bovine medulla and found to be tightly associated with the granule apical surface. MVI also localized to secretory granules within rat pheochromocytoma PC12 cells as well as to the Golgi apparatus, endoplasmic reticulum and clathrin-coated pits. Notably, it was also found in the nucleus. RT-PCR revealed that MVI splice variants with a large insert (LI), characteristic of polarized cells, were barely detectable in PC12 cells, whereas variants with a small insert (SI) were the major isoforms. The presented data indicate that MVI in adrenal medulla cells is engaged in secretory vesicle trafficking within the cytoplasm and possibly also involved in transport within the nucleus.
5

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

81%
Maciag F., Majewski L., Boguszewski P. M., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
|
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).
6

Profile expression of STIM2.1, a newly discovered STIM2 splice variant in immune cells, in mouse brain structures at different times of development

81%
Majewski L., Wasilewska I., Niemeyer B. A., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2017
|
tom 77
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nr Suppl.1
INTRODUCTION: STIM1 and STIM2 mediate the process of store-operated calcium entry (SOCE) by interacting with the ion channels in the cell membrane – ORAIs. SOCE is a process by which the depletion of Ca2+ from the ER causes an influx of Ca2+ from the extracellular space to replenish the intracellular stores. In T cells there are two splice variants of STIM2 – STIM2.1 and STIM2.2, which play opposite roles in regulation of SOCE. According to a paper by Niemeyer group, STIM2.1, in contrast to STIM2.2, has an inhibitory effect on Store‑Operated Calcium Entry (SOCE). AIM(S): One of our objectives was to check the distribution of STIM2.1 and STIM2.2 in mouse brain structures at different times of development. We also investigated the influence of neuronal‑specific STIM1 and ORAI1 overexpression on STIM2 mRNA level in the brain. METHOD(S): Using quantitative RealTime-PCR we compared the expression of STIM2 isoforms in wildtype and our novel transgenic mouse lines overexpressing STIM1 or ORAI1 specifically in brain neurons. RESULTS: We show that STIM2.1 splice variant is expressed in mouse brain at a low level with the highest STIM2.1/STIM2.2 ratio in the olfactory bulbs. These are the only structures in which expression of both STIM2 splice variants increases with aging. We also observed that overexpression of STIM1 in neurons tends to modify the expression of STIM2 isoforms in a region specific manner, eg. it decreases its level in the hippocampus, while increases in substantia nigra. Neither expression of STIM2.2 nor STIM2.1 isoform was affected by ORAI1 overexpression in brain neurons. CONCLUSIONS: Our data show for the first time the expression of STIM2 isoforms in mouse brain structures at different time points. The observation that STIM1 shapes the expression of STIM2 isoforms in a region specific manner could contribute to a better understanding of the interplay between these two key elements of SOCE in neurons. FINANCIAL SUPPORT: This work was supported by funds from Maestro grant to JK from a National Science Centre (2011/02/A/NZ3/00144). The transgenesis was performed in the Laboratory of Animal Models – Nencki Institute of Experimental Biology Polish Academy of Sciences, Warsaw, Poland. We thank Prof. Dr. Barbara Niemeyer for hosting MSc. Iga Wasilewska in her laboratory in the framework of Short Term Mission funded by COST BM1406 action and providing us with the primers sequence of STIM2.1 and STIM2.2.
7

Hybrydowy styropianowy – „Celupan”

71%
Danecki L., Czapiewski G., Wardzinska E., Szczepaniak B., Majewski L.
Biuletyn Informacyjny Ośrodka Badawczo-Rozwojowego Przemysłu Płyt Drewnopochodnych w Czarnej Wodzie
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2016
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tom 57
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nr 1-2
8

STIM1, STIM2 and Orai1-overexpression of key store operated calcium entry in transgenic mice brain

61%
Majewski L., Wiera G., Wojtowicz T., Boguszewski P. M., Mozrzymas J., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. At least two types of AD can be distinguished: sporadic AD (SAD) of unknown etiology, which accounts for most cases, and genetically encoded familial AD (FAD), which affects up to 5% of all patients. Altered calcium homeostasis in neurons is proposed to be one of the early events responsible for AD. Disturbances in Ca2+ signaling are found in SAD patients before any obvious extracellular Aβ pathology; moreover, Ca2+ dysfunction augments Aβ formation and Tau hyperphosphorylation. One of the objectives of our present project is to understand how elevated basal Ca2+ level in neurons contributes to neurodegeneration. METHODS: Generation of transgenic mice using DNAmicroinjection technique. RESULTS: We have generated three transgenic mouse lines independently overexpressing,specifically in brain neurons, key proteins of SOCE – STIM1, STIM2 and Orai1. The phenotype of these mice is being analyzed by electrophysiology, behavior and Ca2+ imaging. Our group has shown that the cytoplasmic resting Ca2+ level in cultured neurons can be modulated by overexpression of STIM proteins, ER Ca2+ sensors involved in the Store Operated Calcium Entry (SOCE). We also detected the enhanced magnitude of Ca2+ influx during SOCE in human lymphocytes from SAD patients, and decreased level of STIM2 protein in human lymphocytes from FAD patients in parallel to an attenuation of SOCE. CONCLUSIONS: The obtained lines can be a suitable model to verify the hypothesis that brain dysfunction during ageing is induced by changes in Ca2+ homeostasis.
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