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Claude-Alain Maurage

Publications and source records attributed to Claude-Alain Maurage.

16 recordsLinked to original sources
PubMed2006

Pin1 allows for differential Tau dephosphorylation in neuronal cells.

Neurofibrillary degeneration is likely to be related to abnormal Tau phosphorylation and aggregation. Among abnormal Tau phosphorylation sites, pThr231 is of particular interest since it is associated with early stages of Alzheimer's disease and is a binding site of Pin1, a peptidyl-prolyl cis/trans isomerase mainly involved in cell cycle regulation. In the present work, Pin1 level was found strongly increased during neuronal differentiation and tightly correlated with Tau dephosphorylation at Thr231. Likewise, we showed in cellular model that Pin1 allowed for specific Tau dephosphorylation at Thr231, whereas other phosphorylation sites were unchanged. Moreover, cells displaying Tau phosphorylation at Thr231 did not show any Pin1 nuclear depletion. Altogether, these data indicate that Pin1 has key function(s) in neuron and is at least involved in the regulation of Tau phosphorylation at relevant sites. Hence, Pin1 dysfunction, unlikely by nuclear depletion, may have critical consequences on Tau pathological aggregation and neuronal death.

Alzheimer Disease↗
PubMed2006

Increasing of HER2 membranar density in human glioblastoma U251MG cell line established in a new nude mice model.

Glioblastoma multiform (GBM) remains the most devastating primary tumour in neuro-oncology. Human Epithelial Receptor Type 2 (HER2) is a transmembrane tyrosine/kinase receptor that is important for cancer growth. HER2 is not expressed in adult glial cells, but its expression increases with the degree of astrocytomas anaplasia. We have recently demonstrated the ability of anti-HER2 antibodies to induce in vitro apoptosis GBM cell lines; this ability is correlated to HER2 density. A decreasing of tyrosine/kinase receptors density during in vitro culture was reported. No information exists about the variation of HER2 expression after in vivo implantation. For that, the two cell lines in vitro tested (U251MG, A172) were in vivo implanted. We established a U251MG in vivo model in balb/c nude mice showing an important increasing of HER2 density. The HER2 density is correlated to anti-HER2 antibody efficiency so this model will be useful for the evaluation of in vivo anti-HER2 antibody treatment.

Animals↗
PubMed2005

Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1.

Alternative splicing is altered in myotonic dystrophy of type 1 (DM1), a syndrome caused by an increase of CTG triplet repeats in the 3' untranslated region of the myotonic dystrophy protein kinase gene. Previously, we reported the preferential skipping of Tau exon 2 in DM1 brains. In this study, we analyze the alternative splicing of Tau exon 6 which can be inserted in three different forms (c, p and d) depending on the 3' splice site used. In fact, inclusion of exon 6c decreases in DM1 brains compared to control brains whereas inclusion of 6d increases. Alteration of exon 6 splicing was not observed in DM1 muscle although this exon was inserted in RNAs from normal muscle and DM1 splicing alterations were first described in this organ. In contrast, alteration of exon 2 of Tau mRNA was observed in both muscle and brain. However, co-transfections of a minigene containing exon 6 with CELF or MBNL1 cDNAs, two splicing factor families suspected to be involved in DM1, showed that they influence exon 6 splicing. Altogether, these results show the importance of determining all the exons and organs targeted by mis-splicing to determine the dysregulation mechanisms of mis-splicing in DM1.

Alternative Splicing↗
PubMed2005

Fiber-type differences in masseter muscle associated with different facial morphologies.

BACKGROUND: The influence of muscle forces and associated physiologic behaviors on dental and skeletal development is well recognized but difficult to quantify because of the limited understanding of the interrelationships between physiologic and other mechanisms during growth. METHODS: The purpose of this study was to characterize fiber-type composition of masseter muscle in 44 subjects during surgical correction of malocclusion. Four fiber types were identified after immunostaining of biopsy sections with myosin heavy chain-specific antibodies, and the average fiber diameter and percentage of muscle occupancy of the fiber types were determined in each of 6 subject groups (Class II or Class III and open bite, normal bite, or deepbite). A 2 x 3 x 4 analysis of variance was used to determine significant differences between mean areas for fiber types, vertical relationships, and sagittal relationships. RESULTS: There were significant differences in percentage of occupancy of fiber types in masseter muscle in bite groups with different vertical dimensions. Type I fiber occupancy increased in open bites, and conversely, type II fiber occupancy increased in deepbites. The association between sagittal jaw relationships and mean fiber area was less strong, but, in the Class III group, the average fiber area was significantly different between the open bite, normal bite, and deepbite subjects. In the Class III subjects, type I and I/II hybrid fiber areas were greatly increased in subjects with deepbite. CONCLUSIONS: Given the variation between subjects in fiber areas and fiber numbers, larger subject populations will be needed to demonstrate more significant associations between sagittal relationships and muscle composition. However, the robust influence of jaw-closing muscles on vertical dimension allowed us to conclude that vertical bite characteristics vary according to the fiber type composition of masseter muscle.

Adult↗
PubMed2005

Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability.

Sporadic Parkinson disease (sPD) is characterized by alpha-synuclein (alpha-syn) inclusions. The distribution of such inclusions appears to relate to disease progression and severity. We propose and test a simple staging protocol based on the presence of alpha-syn immunoreactivity in 5 paraffin sections that, taken together, contain up to 8 vulnerable brain regions. Six stages of alpha-syn pathology reminiscent for sPD are defined based on the presence or absence of inclusions in the assessed sections. Six observers from 5 different institutions rated 21 cases on the basis of written instructions only. The agreement of the raters was highly significant with a mean error below one stage. Both inter- and intra-rater reliability were also substantial to almost perfect as analyzed by paired comparison between all raters. We propose that the staging procedure for alpha-syn pathology is suitable for application in routine neuropathology and brain banking. Clearly defined stages of alpha-synpathology might aid the comparability between studies and also help to distinguish sPD from other synucleinopathies.

Aged↗
PubMed2004

Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis.

The B-Raf(V599E)-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409-42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of (V599E)B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of (V599E)B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.

Base Sequence↗
PubMed2004

Primary amyloidoma of the axis and acute spinal cord compression: a case report.

BACKGROUND: Localized primary amyloidosis is a disease characterized by a single tumor and localized amyloid deposit (amyloidoma) with no evidence of generalized amyloidosis. The occurrence of an amyloidoma in the spine is rare and only three cases affecting the axis have been previously reported. We describe the case of a 79-year-old woman presenting with a mass involving the odontoid process, responsible for an acute tetraparesia. Diagnosis of local primary amyloidosis was made after surgical excision. RESULTS: Despite the critical presentation, outcome was excellent after total excision of the mass. This case can be classified as a primary localized amyloidoma. The patient did not exhibit any infection, tumor or inflammatory disease, and continued investigations failed to demonstrate other amyloid deposit after one-year follow-up. CONCLUSIONS: Amyloidoma must be discussed in presence of a tumor-like mass of the odontoid process and may be responsible, as in our case, for spinal cord compression.

Aged↗
PubMed2003

Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease.

Argyrophilic grain disease (AGD) is characterized by the occurrence of argyrophilic grains and coiled bodies in brain tissue, mainly in limbic areas located in the temporal lobe. Recent biochemical data have shown that inclusions in AGD consist of aggregates of pathological microtubule-associated tau protein isoforms of 64/69 kDa. We report here a study on two AGD patients, belonging to a series of demented patients affected by several tauopathies, prospectively followed until death. In both patients, clinical, neuropathological and biochemical investigations clearly demonstrated AGD. Diffuse tau pathology was shown by Gallyas' silver stain, tau immunohistochemistry and tau protein variant biochemical analysis, not only in temporal lobes but also in all cortical and subcortical areas that were assessed. Primary motor, primary sensory, and associative brain cortices were involved, as well as brain stem, but not cerebellum. We suggest that "diffuse" AGD might be a subgroup of AGD, the specific profile of which is different from that of "limbic" AGD.

Aged↗
PubMed2003

Retinal involvement in dementia with Lewy bodies: a clue to hallucinations?

Visual hallucinations are a core feature of dementia with Lewy bodies. Their pathophysiology is not well understood, because neither clinical nor histological data have shown their basic mechanisms. Here, we report the presence of pale inclusions in the outer plexiform layer of the retina in a patient with dementia with Lewy bodies. These inclusions are related to cytoskeletal disorganization of the cones at ultrastructural level and modifications of the immunohistochemical pattern of distribution of synucleins in the retina. These modifications may participate in the visual impairment in dementia with Lewy bodies.

Brain↗
PubMed2003

Transpupillary thermotherapy (TTT) with short duration laser exposures induce heat shock protein (HSP) hyperexpression on choroidoretinal layers.

BACKGROUND AND OBJECTIVES: To assess a choroidal heat shock protein hyperexpression after transpupillary thermotherapy (TTT) performed with exposures shorter than 60 seconds. STUDY DESIGN/MATERIALS AND METHODS: Nine male pigmented rabbits were anesthetized and TTT was performed on their right eye with a 810 nm diode laser (Iridis, Quantel-Medical (France)) (spot size: 1.3 mm). Three exposure durations (60, 30, or 15 seconds) were used with three ranges of power for each duration ("high," "mild," or "low"). A series of laser impacts was delivered to the posterior pole of the retina. Left eyes were used as controls. Twenty-four hours after laser irradiation, the animals were killed and histological study was performed on chorioretinal layers. Tissue samples were fixed in formalin and embedded in paraffin. A monoclonal antibody was used to detect Hsp70 immunoreactivity (mouse IgGl, SPA-810, Stress Gen, Victoria, BC, Canada), followed by a biotinylated goat anti-mouse antibody (Dako, Glostrup, Denmark), revealed by the avidin-biotin complex (Vectastain kit, Vector Laboratries, Burlingame, CA, USA) and the AEC chromogen. Retinal structures were further identified by HES coloration. RESULTS: During the experiments, the laser spots were not visible except for the strongest "high" powers for each exposure duration, where a whitening was discernable at the end of the laser exposures. A strong HSP70 immunoreactivity was detected in choroidal, non-pigmented cells for laser exposures lasting 60, 30, or 15 seconds with "mild" laser powers. On the contrary, rare HSP hyperexpression was detected with "high" or "low" laser powers lasting 60, 30, or 15 seconds. No HSP-70 immunoreactivity was detected on control eyes nor outside of the irradiated zones of treated eyes. CONCLUSIONS: Transpupillary laser irradiation lasting 15, 30, or 60 seconds induces an hyperexpression of HSP on choroidal layers. This could be a basis for the use of TTT with "short" laser exposures.

Animals↗
PubMed2003

Expression of the c-kit receptor in choroidal melanomas.

The KIT gene encodes c-kit, a transmembrane receptor that has tyrosine kinase activity and plays a role in haematopoiesis, gametogenesis and melanogenesis. The c-kit protein is found in normal cutaneous and choroidal melanocytes, and there is evidence that expression is lost in melanoma. Expression of c-kit was analysed in 57 paraffin-embedded sections of choroidal melanoma specimens and three choroidal melanoma cell lines using immunochemistry and Western blotting. Of the tumour specimens, 75% stained positively for c-kit with a membrane pattern of reactivity. Of the six patients who underwent proton beam therapy before enucleation, five tumours exhibited no c-kit immunoreactivity and the other tumour demonstrated weak staining. Of the three melanoma cell lines used, c-kit expression was observed in only one. No correlations between c-kit positivity and parameters such as cell type, largest macroscopic tumour dimension, scleral invasion or pigmentation were observed. In contrast, a significant positive association was found between c-kit staining and mitotic activity (P = 0.02). However, c-kit expression did not significantly influence survival when evaluated by univariate analysis. In conclusion, c-kit is expressed in most choroidal melanoma tumours. Further analysis should provide new insights into the mechanisms underlying the molecular and cellular changes in choroidal melanomas.

Blotting, Western↗
PubMed2002

Phosphorylated serine 199 of microtubule-associated protein tau is a neuronal epitope abundantly expressed in youth and an early marker of tau pathology.

Microtubule-associated protein tau is abnormally phosphorylated in many neurodegenerative disorders, and is the major component of neurofibrillary degeneration, a degenerating process with many biochemical phenotypes. The serine 199 (S199) residue of tau is phosphorylated at early and late stages of Alzheimer's disease (AD). We studied the immunohistochemical distribution of this phosphorylated epitope in AD and other neurodegenerative disorders, as well as in controls of different ages. The phosphorylated S199 (S199P) epitope was observed in tau lesions from numerous diseases with neurofibrillary degeneration. This epitope was found to be abundantly expressed in the hippocampus formation in childhood and in young adult brain samples, and more specifically in subsets of neurons vulnerable to neurodegeneration. Interestingly, our data suggests that S199P is particularly resistant to phosphatase activity occurring during post-mortem delays. We suggest a peculiar and important role of the S199 residue as a qualitative indicator of the normal and pathological phosphorylation status of tau proteins.

Adolescent↗
PubMed2002

Bilateral multifocal uveal juvenile xanthogranuloma in a young boy with systemic disease.

BACKGROUND: Juvenile xanthogranuloma is a rare non-Langerhans cell histiocytosis that could occasionally produce diffuse systemic disease in young children, but associated posterior uveal lesions are very uncommon. METHODS: Case report of an 8-month-old boy with macrocephaly who presented with chronic subdural haematoma and intracranial hypertension. A combination of nodular skin lesions and bilateral yellowish choroidal infiltration with limited retinal involvement suggested juvenile xanthogranuloma. RESULTS: The diagnosis was confirmed by a skin biopsy, and oral corticosteroid therapy was introduced. Progression of the disease to involve an anterior uveitis with hypopyon and numerous other systemic lesions, including the central nervous system, lung, liver, spleen, kidney and testis, was also suggestive of Letterer-Siwe disease. Histiocytes were negative for Langerhans cell markers (S-100 and CD1a) and positive for macrophage marker (CD68). Electron microscopy failed to show Birbeck granules. Ocular lesions regressed under prolonged corticosteroid treatment, but resurgence of the other lesions required chemotherapy with vinblastine. CONCLUSION: In this atypical systemic variant of juvenile xanthogranuloma with bilateral uveal involvement, the immunohistochemical and ultrastructural findings were crucial in distinguishing juvenile xanthogranuloma from Langerhans cell histiocytosis.

Biopsy↗
PubMed2002

Pin1: a therapeutic target in Alzheimer neurodegeneration.

In Alzheimer's disease, the peptidyl prolyl cis/trans isomerase Pin1 binds to phospho-Thr231 on Tau proteins and, hence, is found within degenerating neurons, where it is associated to the large amounts of abnormally phosphorylated Tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated Tau. In the present work, we investigated, both at the cellular and molecular levels, the role of Pin1 in Alzheimer's disease through the study of its interactions with phosphorylated Tau proteins. We also showed that in neuronal cells, Pin1 upregulates the expression of cyclin D1. This, in turn, could facilitate the transition from quiescence to the G1 phase (re-entry in cell cycle) in a neuron and, subsequently, neuronal dedifferentiation and apoptosis. The involvement of Pin1 in the G0/G1 transition in neurons points to its function as a good target for the development of new therapeutic strategies in neurodegenerative disorders.

Alzheimer Disease↗
PubMedDate not supplied

Tau aggregation in the hippocampal formation: an ageing or a pathological process?

Tauopathy is a concept to describe different genetic or metabolic dysfunctions of tau proteins that generate most of the known dementing disorders. Tauopathy is a degenerating process that also affects the entorhinal formation, and then the hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to APP dysfunction, a similar tauopathy process in observed in neocortical areas, well correlated to cognitive impairment. One important gap of knowledge is the relationship between tauopathy in the hippocampal formation, ageing, AD, and cognitive impairment. Here we show that the multidisciplinary analysis of numerous brains from non-demented and demented patients suggests the following observations: tauopathy of the hippocampal formation in humans is age-related but not an age-dependent process, also independent of AD, but amplified by APP dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be another type of pathological dysfunction of tau proteins, and a therapeutic target to delay AD. Relevant animal models are desperately needed to address this issue.

Aged↗