Laboratoire Dhistologie Et Of Cytogenetique

Limoges, France

Laboratoire Dhistologie Et Of Cytogenetique

Limoges, France
SEARCH FILTERS
Time filter
Source Type

Terro F.,University of Monastir | Terro F.,Laboratoire Dhistologie Et Of Cytogenetique | Magnaudeix A.,University of Monastir | Crochetet M.,University of Monastir | And 8 more authors.
Toxicology | Year: 2012

The expanding use of GSM devices has resulted in public concern. Chaperone-mediated autophagy (CMA) is a way for protein degradation in the lysosomes and increases under stress conditions as a cell defense response. α-synuclein, a CMA substrate, is a component of Parkinson disease. Since GSM might constitute a stress signal, we raised the possibility that GSM could alter the CMA process. Here, we analyzed the effects of chronic exposure to a low GSM-900. MHz dose on apoptosis and CMA. Cultured cerebral cortical cells were sham-exposed or exposed to GSM-900. MHz at specific absorption rate (SAR): 0.25. W/kg for 24. h using a wire-patch cell. Apoptosis was analyzed by DAPI stain of the nuclei and western blot of cleaved caspase-3. The expression of proteins involved in CMA (HSC70, HSP40, HSP90 and LAMP-2A) and α-synuclein were analyzed by western blot. CMA was also quantified in situ by analyzing the cell localization of active lysosomes. 24. h exposure to GSM-900. MHz resulted in ~0.5°C temperature rise. It did not induce apoptosis but increased HSC70 by 26% and slightly decreased HSP90 (<10%). It also decreased α-synuclein by 24% independently of CMA, since the localization of active lysosomes was not altered. Comparable effects were observed in cells incubated at 37.5°C, a condition that mimics the GSM-generated temperature rise. The GSM-induced changes in HSC70, HSP90 and α-synuclein are most likely linked to temperature rise. We did not observe any immediate effect on cell viability. However, the delayed and long term consequences (protective or deleterious) of these changes on cell fate should be examined. © 2011 Elsevier Ireland Ltd.


Wilson C.M.,University of Limoges | Wilson C.M.,Laboratoire Dhistologie Et Of Cytogenetique | Magnaudeix A.,University of Limoges | Yardin C.,University of Limoges | And 3 more authors.
Journal of Biological Chemistry | Year: 2011

The oligosaccharyltransferase complex catalyzes the transfer of oligosaccharide from a dolichol pyrophosphate donor en bloc onto a free asparagine residue of a newly synthesized nascent chain during the translocation in the endoplasmic reticulum lumen. The role of the less known oligosaccharyltransferase (OST) subunits, DC2 and KCP2, recently identified still remains to be determined. Here, we have studied DC2 and KCP2, and we have established that DC2 and KCP2 are substrate-specific, affecting amyloid precursor protein (APP), indicating that they are not core components required for N-glycosylation and OST activity per se. We show for the first time that DC2 and KCP2 depletion affects APP processing, leading to an accumulation of C-terminal fragments, both C99 and C83, and a reduction in full-length mature APP. This reduction in mature APP levels was not due to a block in secretion because the levels of sAPPα secreted into the media were unaffected. We discover that DC2 and KCP2 depletion affects only the γ-secretase complex, resulting in a reduction of the PS1 active fragment blocking Aβ production. Conversely, we show that the overexpression of DC2 and KCP2 causes an increase in the active γ-secretase complex, particularly the N-terminal fragment of PS1 that is generated by endoproteolysis, leading to a stimulation of Aβ production upon overexpression of DC2 and KCP2. Our findings reveal that components of the OSTcomplex for the first time can interact with the γ-secretase and affect the APP processing pathway. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Martin L.,University of Monastir | Magnaudeix A.,University of Monastir | Wilson C.M.,University of Monastir | Wilson C.M.,Laboratoire Dhistologie Et Of Cytogenetique | And 4 more authors.
Journal of Neuroscience Research | Year: 2011

Alterations in glycogen synthase kinase-3β (GSK3β) and protein phosphatase-2A (PP2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation linked to Alzheimer's disease (AD). Interconnections between GSK3β and PP2A signaling pathways are well established. Targeting tau kinases was proposed to represent a therapeutic strategy for AD. However, which tau kinases should be blocked and to what extent, keeping in mind that kinases have physiological roles? Because most kinase inhibitors are relatively specific and many of them interfere with the cell cycle, it is necessary to develop more specific tau kinase inhibitors devoid of cell toxicity. Here, we used the PP2A inhibition by okadaic acid (OKA) in primary cultured cortical neurons as an in vitro model of increased tau phosphorylation and apoptosis. We tested the effects of two newly characterized indirubin derivative inhibitors of GSK3, 6-BIDECO (6-bromoindirubin-3'-[O-(N,N-diethylcarbamyl)-oxime] and 6-BIMYEO (6-bromoindirubin-3'-[O-(2-morpholin-1-ylethyl)-oxime] hydrochloride) on OKA-induced tau phosphorylation and neuronal apoptosis. Both compounds exhibit higher selectivity toward GSK3 compared with other tau kinases (for 6-BIDECO, IC50 is 0.03 μM for GSK3, >10 μM for CDK1, and 10 μM for CDK5; for 6-BIMYEO, IC50 is 0.11 μM for GSK3, 1.8 μM for CDK1, and 0.9 μM for CDK5). We show that 6-BIDECO and 6-BIMYEO used at micromolar concentrations are not neurotoxic and potently reversed tau phosphorylation and apoptosis induced by OKA. The neuroprotection by these compounds should be further validated in animal models of AD. © 2011 Wiley-Liss, Inc.


Martin L.,University of Monastir | Latypova X.,University of Monastir | Terro F.,University of Monastir | Terro F.,Laboratoire Dhistologie Et Of Cytogenetique
Neurochemistry International | Year: 2011

Alzheimer's disease (AD) belongs to a group of neurodegenerative diseases collectively designated as "tauopathies", because they are characterized by the aggregation of abnormally phosphorylated tau protein. The mechanisms responsible for tau aggregation and its contribution to neurodegeneration are still unknown. Thereby, understanding the modes of regulation of tau is of high interest in the determination of the possible causes at the origin of the formation of tau aggregates and to elaborate protection strategies to cope with these pathological lesions. The regulation of tau takes place predominantly through post-translational modifications. Extensive reports have been published about tau phosphorylation; however, the other tau post-translational modifications have received much less attention. Here, we review the different types of post-translational modifications of tau including phosphorylation, glycosylation, glycation, prolyl-isomerization, cleavage or truncation, nitration, polyamination, ubiquitination, sumoylation, oxidation and aggregation, with a particular interest towards their relevance in AD. © 2011 Elsevier Ltd. All rights reserved.


Martin L.,University of Monastir | Martin L.,Laboratoire Dhistologie Et Of Cytogenetique | Martin L.,University of Nantes | Martin L.,French Institute of Health and Medical Research | And 7 more authors.
Ageing Research Reviews | Year: 2013

Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby that might contributes to tau aggregation. Thus, understanding the regulation modes of tau dephosphorylation is of high interest in determining the possible causes at the origin of the formation of tau aggregates and to elaborate protection strategies to cope with these lesions in AD. Among the possible and relatively specific interventions that reverse tau phosphorylation is the stimulation of certain tau phosphatases. Here, we reviewed tau protein phosphatases, their physiological roles and regulation, their involvement in tau phosphorylation and the relevance to AD. We also reviewed the most common compounds acting on each tau phosphatase including PP2A. © 2012 Elsevier B.V.


Martin L.,University of Monastir | Martin L.,Laboratoire Dhistologie Et Of Cytogenetique | Martin L.,University of Nantes | Martin L.,French Institute of Health and Medical Research | And 9 more authors.
Ageing Research Reviews | Year: 2013

Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby might contribute to tau aggregation. Thus, understanding the regulation modes of tau phosphorylation is of high interest in determining the possible causes at the origin of the formation of tau aggregates in order to elaborate protection strategies to cope with these lesions in Alzheimer's disease. Among the possible and specific interventions that reverse tau phosphorylation is the inhibition of certain tau kinases. Here, we extensively reviewed tau protein kinases, their physiological roles and regulation, their involvement in tau phosphorylation and their relevance to AD. We also reviewed the most common inhibitory compounds acting on each tau kinase. © 2012 Elsevier B.V.


Martin L.,University of Monastir | Page G.,Groupe de Recherche sur le Vieillissement Cerebral | Terro F.,University of Monastir | Terro F.,Laboratoire Dhistologie Et Of Cytogenetique
Neurochemistry International | Year: 2011

Overactivation of GSK3β (glycogen synthase kinase-3β) and downregulation of PP2A (protein phosphatase-2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation in Alzheimer's disease (AD). GSK3β and PP2A signaling pathways were reported to be interconnected. Targeting tau kinases was suggested to represent a therapeutic strategy for AD. Here, tau phosphorylation and neuronal apoptosis were induced in cortical cultured neurons by the inhibition of PP2A by okadaic acid (OKA). In this in vitro model of 'tau pathology' and neurodegeneration, we tested whether GSK3β and other tau kinases including DYRK1A and CDK5 were implicated. Our results show that the inhibitors of GSK3β, lithium and 6-BIO (6-bromoindirubin-3′-oxime), prevented OKA-induced tau phosphorylation and neuronal apoptosis. The implication of GSK3β in these OKA-induced effects was confirmed by its silencing by hairpin siRNA. By contrast, inhibition of DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase-1A) and CDK5 (cyclin-dependent kinase-5) reversed OKA-induced tau phosphorylation at certain sites but failed to prevent neuronal apoptosis. These results indicate that OKA-induced effects, especially neuronal apoptosis, are preferentially mediated by GSK3β. Furthermore, since chronic exposure to lithium and 6-BIO might be deleterious for neurons, we tested the effect of a new 6-BIO derivative, 6-BIBEO (6-bromoindirubin-3′-(2-bromoethyl)-oxime), which is much less cytotoxic and more selectively inhibits GSK3β compared to lithium and 6-BIO. We show that 6-BIBEO efficiently reversed OKA-induced tau phosphorylation and neuronal apoptosis. It will be interesting to test neuroprotection by 6-BIBEO in an in vivo model of tau pathology and neurodegeneration. © 2011 Elsevier B.V. All rights reserved.

Loading Laboratoire Dhistologie Et Of Cytogenetique collaborators
Loading Laboratoire Dhistologie Et Of Cytogenetique collaborators