Danielle Seilhean

L'Institut du Cerveau et de la Moelle Épinière, Lutetia Parisorum, Île-de-France, France

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Publications (121)636.46 Total impact

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    ABSTRACT: Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyotrophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglial cells influence disease progression. However, microglial-derived neurotoxic factors still remain largely unidentified in amyotrophic lateral sclerosis. With excitotoxicity being a major mechanism proposed to cause motor neuron death in amyotrophic lateral sclerosis, our hypothesis was that excessive glutamate release by activated microglia through their system [Formula: see text] (a cystine/glutamate antiporter with the specific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we show that xCT expression is enriched in microglia compared to total mouse spinal cord and absent from motor neurons. Activated microglia induced xCT expression and during disease, xCT levels were increased in both spinal cord and isolated microglia from mutant SOD1 amyotrophic lateral sclerosis mice. Expression of xCT was also detectable in spinal cord post-mortem tissues of patients with amyotrophic lateral sclerosis and correlated with increased inflammation. Genetic deletion of xCT in mice demonstrated that activated microglia released glutamate mainly through system [Formula: see text]. Interestingly, xCT deletion also led to decreased production of specific microglial pro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, whereas expression of anti-inflammatory/neuroprotective markers such as Ym1/Chil3 were increased, indicating that xCT regulates microglial functions. In amyotrophic lateral sclerosis mice, xCT deletion surprisingly led to earlier symptom onset but, importantly, this was followed by a significantly slowed progressive disease phase, which resulted in more surviving motor neurons. These results are consistent with a deleterious contribution of microglial-derived glutamate during symptomatic disease. Therefore, we show that system [Formula: see text] participates in microglial reactivity and modulates amyotrophic lateral sclerosis motor neuron degeneration, revealing system [Formula: see text] inactivation, as a potential approach to slow amyotrophic lateral sclerosis disease progression after onset of clinical symptoms.
    Brain : a journal of neurology. 11/2014;
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    ABSTRACT: The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
    Journal of Neural Transmission 09/2014; · 3.05 Impact Factor
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    ABSTRACT: Neurodegenerative diseases of the central nervous system are characterized by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues. The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases. The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases. This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
    Journal of Neural Transmission 08/2014; · 3.05 Impact Factor
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    ABSTRACT: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.
    Neurology 08/2014; · 8.30 Impact Factor
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    ABSTRACT: Background Although thrombosis is considered the cardinal feature of the antiphospholipid syndrome, chronic vascular lesions are common, particularly in patients with life-threatening complications. In patients who require transplantation, vascular lesions often recur. The molecular pathways involved in the vasculopathy of the antiphospholipid syndrome are unknown, and adequate therapies are lacking. Methods We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. We also evaluated autopsy specimens from persons who had catastrophic antiphospholipid syndrome. The molecular pathways through which antiphospholipid antibodies modulate the mTORC pathway were evaluated in vitro, and potential pharmacologic inhibitors were also tested in vitro. Finally, we studied the effect of sirolimus in kidney-transplant recipients with the antiphospholipid syndrome. Results The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome. Conclusions Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. (Funded by INSERM and others.).
    New England Journal of Medicine 07/2014; 371(4):303-312. · 54.42 Impact Factor
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    ABSTRACT: There is still no treatment for polyglutamine disorders, but clearance of mutant proteins might represent a potential therapeutic strategy. Autophagy, the major pathway for organelle and protein turnover, has been implicated in these diseases. To determine whether the autophagy/lysosome system contributes to the pathogenesis of spinocerebellar ataxia type 7 (SCA7), caused by expansion of a polyglutamine tract in the ataxin-7 protein, we looked for biochemical, histological and transcriptomic abnormalities in components of the autophagy/lysosome pathway in a knock-in mouse model of the disease, postmortem brain and peripheral blood mononuclear cells (PBMC) from patients. In the mouse model, mutant ataxin-7 accumulated in inclusions immunoreactive for the autophagy-associated proteins mTOR, beclin-1, p62 and ubiquitin. Atypical accumulations of the autophagosome/lysosome markers LC3, LAMP-1, LAMP2 and cathepsin-D were also found in the cerebellum of the SCA7 knock-in mice. In patients, abnormal accumulations of autophagy markers were detected in the cerebellum and cerebral cortex of patients, but not in the striatum that is spared in SCA7, suggesting that autophagy might be impaired by the selective accumulation of mutant ataxin-7. In vitro studies demonstrated that the autophagic flux was impaired in cells overexpressing full-length mutant ataxin-7. Interestingly, the expression of the early autophagy-associated gene ATG12 was increased in PBMC from SCA7 patients in correlation with disease severity. These results provide evidence that the autophagy/lysosome pathway is impaired in neurons undergoing degeneration in SCA7. Autophagy/lysosome-associated molecules might, therefore, be useful markers for monitoring the effects of potential therapeutic approaches using modulators of autophagy in SCA7 and other autophagy/lysosome-associated neurodegenerative disorders.
    Acta Neuropathologica 05/2014; · 9.73 Impact Factor
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    ABSTRACT: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
    Acta Neuropathologica 01/2014; · 9.73 Impact Factor
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    ABSTRACT: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1·1, 95% CI 0·8-1·7, p=0·50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group. Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease. Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
    The Lancet Neurology 01/2014; · 23.92 Impact Factor
  • D Seilhean, F Bielle, I Plu, C Duyckaerts
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a heterogeneous group including both sporadic and familial diseases, characterized by a macroscopic alteration. It may correspond to various cognitive syndromes: behavioral variant of frontotemporal dementia (bvFTD), progressive nonfluent aphasia, and semantic dementia. The neuropathologic classification is now based on identification of the protein that accumulates in neurons and glia: Tau, TAR DNA Binding Protein 43 (TDP-43), and FUsed in Sarcoma (FUS). The disorders in which the corresponding proteins accumulate have been named FTLD-Tau, FTLD-TDP, and FTLD-FUS. FTLD-Tau includes sporadic cases (e.g. Pick's disease) and Tau mutations. FTLD-TDP are subdivided within four types (A, B, C, D) according to the shape and distribution of TDP-43 positive lesions within the associative frontal cortex. The FTLD-FUS group includes atypical FTLD with ubiquitinated lesions (FTLD-U), Neuronal Intermediate Filament Inclusion Disease (NIFID) and Basophilic Inclusion Body Disease (BIBD).
    Revue Neurologique 09/2013; · 0.51 Impact Factor
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    ABSTRACT: We have previously demonstrated that Sox17 expression is prominent at developmental stages corresponding to oligodendrocyte progenitor cell (OPC) cycle exit and onset of differentiation, and that Sox17 promotes initiation of OPC differentiation. In this study, we examined Sox17 expression and regulation under pathological conditions, particularly in two animal models of demyelination/remyelination and in post-mortem multiple sclerosis (MS) brain lesions. We found that the number of Sox17 expressing cells was significantly increased in lysolecithin (LPC)-induced lesions of the mouse spinal cord between 7 and 30 days post-injection, as compared with controls. Sox17 immunoreactivity was predominantly detected in Olig2(+) and CC1(+) oligodendrocytes and rarely in NG2(+) OPCs. The highest density of Sox17(+) oligodendrocytes was observed at 2 weeks after LPC injection, coinciding with OPC differentiation. Consistent with these findings, in cuprizone-treated mice, Sox17 expression was highest in newly generated and in maturing CC1(+) oligodendrocytes, but low in NG2(+) OPCs during the demyelination and remyelination phases. In MS tissue, Sox17 was primarily detected in actively demyelinating lesions and periplaque white matter. Sox17 immunoreactivity was co-localized with NOGO-A+ post-mitotic oligodendrocytes both in active MS lesions and periplaque white matter. Taken together, our data: (i) demonstrate that Sox17 expression is highest in newly generated oligodendrocytes under pathological conditions and could be used as a marker of oligodendrocyte regeneration, and (ii) are suggestive of Sox17 playing a critical role in oligodendrocyte differentiation and lesion repair. GLIA 2013.
    Glia 08/2013; · 5.07 Impact Factor
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    ABSTRACT: AIMS: Although demyelination is an important cause of neurological deficits in Multiple Sclerosis (MS), recently axonal pathology and concomitant involvement of sodium channels (Nav) have become a focus of major interest. Studies in experimental autoimmune encephalomyelitis and MS have shown a diffuse distribution of the expression of two channels, Nav1.6 and Nav1.2, along the demyelinated axons. However, the relationship between the expression of these channels by the axon and its environment are not yet known. The aim of this study was to identify the stage and the neuropathological characteristics of the plaque associated with the changes in sodium channel axonal expression. METHODS: We analysed the expression of Nav1.6 and Nav1.2 along demyelinated axons in 64 plaques from 12 MS cases (compared to 6 control cases) characterized according to the Vienna consensus. We used Bodian silver impregnation combined with Luxol fast blue stain and immunohistochemistry for myelin basic protein, microglia/macrophages, B and T cells, neurofilaments and glial fibrillary acidic protein performed on sections of formalin fixed, paraffin embedded tissue. RESULTS: The presence of axonal diffuse expression of Nav1.6 was more frequent in inflammatory plaques with no active demyelination, and particularly within plaques with T cells and activated microglia. On the other hand, Nav1.2 expression seemed to be independent of the stage and the neuropathological environment of the plaque. CONCLUSIONS: The cellular environment of the axon influences the differential expression of Nav channels. A better understanding on the influence of inflammation on the sodium channels mediated axonal degeneration could offer therapeutic perspectives.
    Neuropathology and Applied Neurobiology 05/2013; · 4.84 Impact Factor
  • Charles Duyckaerts, Danielle Seilhean
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    ABSTRACT: Improvement of the analytical methods and routine use of immunohistochemistry have demonstrated that most neurodegenerative diseases, known to-day, are characterized by the accumulation of one or several specific proteins for example Abeta peptide and Tau protein in Alzheimer disease, alpha-synuclein in Parkinson disease and dementia with Lewy bodies, TDP-43 in a large group of fronto-temporal dementia. In the case of Alzheimer and Lewy body disease, recent data suggest that misfolding of Abeta peptide, of Tau protein or of alpha-synuclein may propagate to the normal protein of the host in a way that reminds the propagation observed in prion diseases.
    La Revue du praticien 05/2013; 63(5):655-61.
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    ABSTRACT: Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget's disease and ALS patients carrying these mutations had both concomitant Paget's disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.
    Acta Neuropathologica 02/2013; · 9.73 Impact Factor
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    ABSTRACT: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
    Journal of Alzheimer's disease: JAD 12/2012; · 4.17 Impact Factor
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    ABSTRACT: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23–50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9–56.1) than in MAPT patients (46.8, 95%CI: 43.0–50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6–61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
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    ABSTRACT: Intracellular inclusions seen by the pathologist may have variable significance. Although they are excellent markers of proteolytic disorders, they can also be due to several other mechanisms. This article examines recent data on the morphology, significance and consequences of aging lipofuscins in the brain and retina, neurofibrillary tangles and Lewy bodies, and Birbeck granules associated with Langerhans histiocytosis. Some of these disorders involve increased protein production, misfolding and aggregation, and altered intracellular proteolysis, but other cell constituents may also play a role. Proteolytic mechanisms do not appear to be involved in the formation of Birbeck granules, which helped to reveal the Langerhans origin of histiocytosis X. Analyses of intracellular inclusions, together with genetic and epigenetic studies, are highly informative in various degenerative diseases.
    Bulletin de l'Académie nationale de médecine 11/2012; 196(8):1575-85; discussion 1585-6. · 0.16 Impact Factor
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    ABSTRACT: The use of an appropriate reference gene to ensure accurate normalisation is crucial for the correct quantification of gene expression using qPCR assays and RNA arrays. The main criterion for a gene to qualify as a reference gene is a stable expression across various cell types and experimental settings. Several reference genes are commonly in use but more and more evidence reveals variations in their expression due to the presence of on-going neuropathological disease processes, raising doubts concerning their use. We conducted an analysis of genome-wide changes of gene expression in the human central nervous system (CNS) covering several neurological disorders and regions, including the spinal cord, and were able to identify a number of novel stable reference genes. We tested the stability of expression of eight novel (ATP5E, AARS, GAPVD1, CSNK2B, XPNPEP1, OSBP, NAT5 and DCTN2) and four more commonly used (BECN1, GAPDH, QARS and TUBB) reference genes in a smaller cohort using RT-qPCR. The most stable genes out of the 12 reference genes were tested as normaliser to validate increased levels of a target gene in CNS disease. We found that in human post-mortem tissue the novel reference genes, XPNPEP1 and AARS, were efficient in replicating microarray target gene expression levels and that XPNPEP1 was more efficient as a normaliser than BECN1, which has been shown to change in expression as a consequence of neuronal cell loss. We provide herein one more suitable novel reference gene, XPNPEP1, with no current neuroinflammatory or neurodegenerative associations that can be used for gene quantitative gene expression studies with human CNS post-mortem tissue and also suggest a list of potential other candidates. These data also emphasise the importance of organ/tissue-specific stably expressed genes as reference genes for RNA studies.
    Acta Neuropathologica 08/2012; · 9.73 Impact Factor
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    ABSTRACT: The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrP(Sc) (i.e. type 1 migrating at 21 kDa and type 2 at 19 kDa). We previously demonstrated that PrP(Sc) typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrP(Sc) types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt-Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100 %) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrP(Sc) typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy.
    Acta Neuropathologica 06/2012; 124(4):517-29. · 9.73 Impact Factor

Publication Stats

2k Citations
636.46 Total Impact Points

Institutions

  • 2013
    • L'Institut du Cerveau et de la Moelle Épinière
      Lutetia Parisorum, Île-de-France, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1997–2013
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Département de Neuropathologie
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Académie Nationale de Médecine
      Lutetia Parisorum, Île-de-France, France
    • University of Eastern Finland
      Kuopio, Eastern Finland Province, Finland
  • 2010–2012
    • Assistance Publique – Hôpitaux de Paris
      • Département de Neuropathologie
      Lutetia Parisorum, Île-de-France, France
  • 2009–2012
    • Imperial College London
      • Division of Brain Sciences
      London, ENG, United Kingdom
    • Harvard Medical School
      • Department of Neurology
      Boston, MA, United States
  • 2011
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1995–2010
    • Pierre and Marie Curie University - Paris 6
      • • Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière
      • • Laboratoire d'histopathologie
      Paris, Ile-de-France, France
  • 2006–2009
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
  • 2008
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2005
    • University of Strasbourg
      • Laboratoire de signalisations moléculaires et neurodégénérescence
      Strasbourg, Alsace, France
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
  • 2001
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 1999
    • Hôpital Raymond-Poincaré – Hôpitaux universitaires Paris Ile-de-France Ouest
      Île-de-France, France