Merle Ruberg

Publications (80)401.39 Total impact

• Article: Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

  Alice Chort, Sandro Alves, Martina Marinello, Béatrice Dufresnois, Jean-Gabriel Dornbierer, Christelle Tesson, Morwena Latouche, Darren P Baker, Martine Barkats, Khalid H El Hachimi, Merle Ruberg, Alexandre Janer, Giovanni Stevanin, Alexis Brice, Annie Sittler
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  ABSTRACT: We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.
  Brain 03/2013; · 9.46 Impact Factor
• Article: The impact of familial structure on Parkinson's disease in Istanbul Medical School, Turkey.

  Ebba Lohmann, Haşmet A Hanağası, Hakan Gürvit, Günes Kayacı, Merle Ruberg, Jale Yazıcı, Murat Emre
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  ABSTRACT: The prevalence and family structure of idiopathic Parkinson disease (iPD) in Turkey is not known. Patients with iPD were recruited consecutively at the Medical School of Istanbul University over an 18-month period. Clinical details were assessed with standardized forms. Of the 219 iPD patients, 136 had sporadic iPD [26 with parental consanguinity (cs)], 20 autosomal recessive PD (9 with cs) and 63 autosomal dominant or pseudo-dominant inheritances (20 with cs). Age at onset was 49.1 ± 17.1 years (range 3-83) and age at examination 56.4 ± 16.5 years (range 4-93). Ages at examination and at clinical onset of PD were significantly greater in sporadic iPD than in familial iPD patients, but disease duration was similar. Patients with familial PD had significantly lower basal UPDRS III and Hoehn and Yahr scores than sporadic PD patients and brisk reflexes in the lower limbs were significantly more frequent, but they suffered less from mictional problems. The frequency of familial PD and consanguinity in Turkey is higher and age at onset of iPD earlier than in Western countries. Molecular diagnoses and genetic counseling will therefore have a very important impact on the medical, psychological, and familial handling of PD in Turkey.
  The International journal of neuroscience 02/2012; 122(2):102-5. · 0.86 Impact Factor
• Article: Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies.

  Matthias Höllerhage, Andreas Matusch, Pierre Champy, Anne Lombès, Merle Ruberg, Wolfgang H Oertel, Günter U Höglinger
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  ABSTRACT: Annonacin, a natural lipophilic inhibitor of mitochondrial complex I has been implicated in the etiology of a sporadic neurodegenerative tauopathy in Guadeloupe. We therefore studied further compounds representing the broad biochemical spectrum of complex I inhibitors to which humans are potentially exposed. We determined their lipophilicity, their effect on complex I activity in submitochondrial particles, and their effect on cellular ATP levels, neuronal cell death and somatodendritic redistribution of phosphorylated tau protein (AD2 antibody against pS396/pS404-tau) in primary cultures of fetal rat striatum. The 24 compounds tested were lipophilic (logP range 0.9-8.5; exception: MPP(+) logP=-1.35) and potent complex I inhibitors (IC(50) range 0.9 nM-2.6 mM). They all decreased ATP levels (EC(50) range 1.9 nM-54.2 microM), induced neuronal cell death (EC(50) range 1.1 nM-54.5 microM) and caused the redistribution of AD2(+) tau from axons to the cell body (EC(5) range 0.6 nM-33.3 microM). The potency of the compounds to inhibit complex I correlated with their potency to induce tau redistribution (r=0.80, p<0.001). In conclusion, we propose that the widely distributed lipophilic complex I inhibitors studied here might be implicated in the induction of tauopathies with global prevalence.
  Experimental Neurology 09/2009; 220(1):133-42. · 4.70 Impact Factor
• Article: Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum.

  Marie-Paule Muriel, Aurélien Dauphin, Michito Namekawa, Annie Gervais, Alexis Brice, Merle Ruberg
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  ABSTRACT: We examined the effects of wild-type and mutant atlastin-1 on vesicle transport in the endoplasmic reticulum (ER)-Golgi interface and vesicle budding from ER-derived microsomes using the temperature-sensitive reporter vesicular stomatitis virus glycoprotein (VSV-G), and the ability of purified atlastin-1 to form tubules or vesicles from protein-free phosphatidylserine liposomes. A GTPase domain mutation (T162P) altered the cellular distribution of the ER, but none of the mutations studied significantly affected transport from the ER to the Golgi apparatus. The mutations also had no significant effect on the incorporation of VSV-G into vesicles formed from ER microsomes. Atlastin-1, however, was also incorporated into microsome-derived vesicles, suggesting that it might be implicated in vesicle formation. Purified atlastin-1 transformed phosphatidylserine liposomes into branched tubules and polygonal networks of tubules and vesicles, an action inhibited by GDP and the synthetic dynamin inhibitor dynasore. The GTPase mutations T162P and R217C decreased but did not totally prevent this action; the C-terminal transmembrane domain mutation R495W was as active as the wild-type enzyme. Similar effects were observed in human embryonic kidney cells over-expressing mutant atlastin-1. We concluded that atlastin-1, like dynamin, might be implicated in membrane tubulation and vesiculation and participated in the formation as well as the function of the ER.
  Journal of Neurochemistry 08/2009; 110(5):1607-16. · 4.06 Impact Factor
• Source

  Available from: Nadia Bahi-Buisson

  Article: Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.

  Christel Depienne, Delphine Bouteiller, Boris Keren, Emmanuel Cheuret, Karine Poirier, Oriane Trouillard, Baya Benyahia, Chloé Quelin, Wassila Carpentier, Sophie Julia, [......], Marie Hélias, Isabelle Py, Serge Rivera, Nadia Bahi-Buisson, Isabelle Gourfinkel-An, Cécile Cazeneuve, Merle Ruberg, Alexis Brice, Rima Nabbout, Eric Leguern
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  ABSTRACT: Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.
  PLoS Genetics 03/2009; 5(2):e1000381. · 8.69 Impact Factor
• Article: In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy.

  Maria Stamelou, Ulrich Pilatus, Alexander Reuss, Jörg Magerkurth, Karla M Eggert, Susanne Knake, Merle Ruberg, Carmen Schade-Brittinger, Wolfgang H Oertel, Günter U Höglinger
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  ABSTRACT: Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N=21; PSP stages II to III) and healthy controls (N=9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (=ATP+phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.
  Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2009; 29(4):861-70. · 5.46 Impact Factor
• Article: The PSP‐associated MAPT H1 subhaplotype in Guadeloupean atypical Parkinsonism

  Agnès Camuzat BS, Marc Romana PhD, PhD Alexandra Dürr MD, Josué Feingold MD, Alexis Brice MD, Merle Ruberg PhD, PhD Annie Lannuzel MD, Agnès Camuzat, Marc Romana, Alexandra Dürr, Josué Feingold, Alexis Brice, Merle Ruberg, Annie Lannuzel
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  ABSTRACT: The aim of this study was to determine whether the H1 subhaplotype in MAPT associated with progressive supranuclear palsy (PSP) in Caucasians confers risk for PSP-like atypical parkinsonism in Guadeloupe, a tauopathy. Guadeloupean controls and patients with atypical and idiopathic parkinsonism and ethnically and age-matched controls were genotyped for H1 and H2 alleles, then for the H1 subhaplotype associated with PSP in Caucasians, using previously described haplotype-tagging single nucleotide polymorphisms (Ht-SNPs) in linkage disequilibrium at the MAPT locus. Most Guadeloupean controls and patients were homozygous for the H1 allele; only 5% were heterozygous for the H2 allele, consistent with the European contribution to the racial admixture in Guadeloupe, but equivalent to the frequency found in Caucasian PSP patients. The frequencies of the Ht-SNPs used to determine the PSP-associated H1 subhaplotype in both Guadeloupean controls and parkinsonians were similar, indicating that the H1 subhaplotype associated with PSP in Caucasians was not a risk factor for PSP-like atypical parkinsonism in Guadeloupe. Interestingly, they were also similar to the frequencies in Caucasian PSP patients. The major H1 subhaplotype in Guadeloupe, determined by analysis of linkage desequibrium, differed from the major Caucasian subhaplotype, but corresponded to minor alleles previously described. © 2008 Movement Disorder Society
  Movement Disorders 12/2008; 23(16):2384 - 2391. · 4.51 Impact Factor
• Article: The PSP-associated MAPT H1 subhaplotype in Guadeloupean atypical parkinsonism.

  Agnès Camuzat, Marc Romana, Alexandra Dürr, Josué Feingold, Alexis Brice, Merle Ruberg, Annie Lannuzel
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  ABSTRACT: The aim of this study was to determine whether the H1 subhaplotype in MAPT associated with progressive supranuclear palsy (PSP) in Caucasians confers risk for PSP-like atypical parkinsonism in Guadeloupe, a tauopathy. Guadeloupean controls and patients with atypical and idiopathic parkinsonism and ethnically and age-matched controls were genotyped for H1 and H2 alleles, then for the H1 subhaplotype associated with PSP in Caucasians, using previously described haplotype-tagging single nucleotide polymorphisms (Ht-SNPs) in linkage disequilibrium at the MAPT locus. Most Guadeloupean controls and patients were homozygous for the H1 allele; only 5% were heterozygous for the H2 allele, consistent with the European contribution to the racial admixture in Guadeloupe, but equivalent to the frequency found in Caucasian PSP patients. The frequencies of the Ht-SNPs used to determine the PSP-associated H1 subhaplotype in both Guadeloupean controls and parkinsonians were similar, indicating that the H1 subhaplotype associated with PSP in Caucasians was not a risk factor for PSP-like atypical parkinsonism in Guadeloupe. Interestingly, they were also similar to the frequencies in Caucasian PSP patients. The major H1 subhaplotype in Guadeloupe, determined by analysis of linkage desequibrium, differed from the major Caucasian subhaplotype, but corresponded to minor alleles previously described.
  Movement Disorders 10/2008; 23(16):2384-91. · 4.51 Impact Factor
• Article: Atypical parkinsonism in the Caribbean island of Guadeloupe: etiological role of the mitochondrial complex I inhibitor annonacin.

  Annie Lannuzel, Merle Ruberg, Patrick P Michel
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  ABSTRACT: On the French West Indian island of Guadeloupe, atypical parkinsonian patients represent two-thirds of all cases of parkinsonism, which is exceptionally frequent compared to epidemiological data from European countries where atypical parkinsonism accounts for only approximately 5% of all cases. The clinical entity was a unique combination of levodopa-resistant parkinsonism, tremor, myoclonus, hallucinations, REM sleep behavior disorder and fronto-subcortical dementia. Based on the presence or the absence of supranuclear gaze palsy, two subgroups of patients were distinguished. In patients with oculomotor signs that came to autopsy, neuronal loss was found to predominate in the substantia nigra and the striatum but other brain areas were also affected, including the frontal cortex. In addition, tau-containing lesions were detected throughout the brain. Epidemiological data suggested a close association of the disease with the regular consumption of soursop, a tropical annonaceous plant. Experimental studies performed in midbrain cell cultures identified annonacin, a selective mitochondrial complex I inhibitor contained in the fruit and leaves of soursop, as a probable etiological factor. Consistent with this view, chronic administration of annonacin to rats through Alzet osmotic minipumps showed that annonacin was able to reproduce the brain lesions characteristic of the human disease.
  Movement Disorders 10/2008; 23(15):2122-8. · 4.51 Impact Factor
• Article: A locus for bilateral occipital polymicrogyria maps to chromosome 6q16-q22.

  Bouchra Ouled Amar Ben Cheikh, Stéphanie Baulac, Fatiha Lahjouji, Ahmed Bouhouche, Philippe Couarch, Naima Khalili, Wafae Regragui, Stéphane Lehericy, Merle Ruberg, Ali Benomar, Simon Heath, Taib Chkili, Mohamed Yahyaoui, Mohamed Jiddane, Reda Ouazzani, Eric LeGuern
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  ABSTRACT: We describe the clinical, radiographic, and genetic features of a large consanguineous Moroccan family in which bilateral occipital polymicrogyria segregated as an autosomal recessive trait. Six affected members of the family had partial complex seizures often associated with behavioral abnormalities. On MRI, three patients had a thickened irregular cortex in the lateral occipital lobes with small gyri. A high-density genome-wide scan with 10,000 SNPs established linkage by homozygosity mapping to a 14-Mb region on chromosome 6q16-q22. Candidate genes by function (TUBE1, GRIK2, GPRC6A, GPR6, NR2E1, MICAL1, and MARCKS) in this locus were screened for mutations.
  Neurogenetics 09/2008; 10(1):35-42. · 3.35 Impact Factor
• Article: Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment.

  Sophie Tezenas du Montcel, Perrine Charles, Pascale Ribai, Cyril Goizet, Alice Le Bayon, Pierre Labauge, Lucie Guyant-Maréchal, Sylvie Forlani, Celine Jauffret, Nadia Vandenberghe, Karine N'guyen, Isabelle Le Ber, David Devos, Carlo-Maria Vincitorio, Mario-Ubaldo Manto, François Tison, Didier Hannequin, Merle Ruberg, Alexis Brice, Alexandra Durr
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  ABSTRACT: Reliable and easy to perform functional scales are a prerequisite for future therapeutic trials in cerebellar ataxias. In order to assess the specificity of quantitative functional tests of cerebellar dysfunction, we investigated 123 controls, 141 patients with an autosomal dominant cerebellar ataxia (ADCA) and 53 patients with autosomal dominant spastic paraplegia (ADSP). We evaluated four different functional tests (nine-hole pegboard, click, tapping and writing tests), in correlation with the scale for the assessment and rating of cerebellar ataxia (SARA), the scale of functional disability on daily activities (part IV of the Huntington disease rating scale), depression (the Public Health Questionnaire PHQ-9) and the EQ-5D visual analogue scale for self-evaluation of health status. There was a significant correlation between each functional test and a lower limb score. The performance of controls on the functional tests was significantly correlated with age. Subsequent analyses were therefore adjusted for this factor. The performances of ADCA patients on the different tests were significantly worse than that of controls and ADSP patients; there was no difference between ADSP patients and controls. Linear regression analysis showed that only two independent tests, the nine-hole pegboard and the click test on the dominant side (P < 0.0001), accounted for the severity of the cerebellar syndrome as reflected by the SARA scores, and could be represented by a composite cerebellar functional severity (CCFS) score calculated as follows: [Formula: see text]. The CCFS score was significantly higher in ADCA patients compared to controls (1.12 +/- 0.18 versus 0.85 +/- 0.05, P(c) < 0.0001) and ADSP patients (1.12 +/- 0.18 versus 0.90 +/- 0.08, P(c) < 0.0001) and was correlated with disease duration (P < 0.0001) but independent of self-evaluated depressive mood in ADCA. Among genetically homogeneous subgroups of ADCA patients (Spinocerebellar ataxia 1, 2, 3), SCA3 patients had significantly lower (better) CCFS scores than SCA2 (P(c) < 0.04) and the same tendency was observed in SCA1. Their CCFS scores remained significantly worse than those of ADSP patients with identified SPG4 mutations (P < 0.0001). The pegboard and click tests are easy to perform and accurately reflect the severity of the disease. The CCFS is a simple and validated method for assessing cerebellar ataxia over a wide range of severity, and will be particularly useful for discriminating paucisymptomatic carriers from affected patients and for evaluating disease progression in future therapeutic trials.
  Brain 06/2008; 131(Pt 5):1352-61. · 9.46 Impact Factor
• Article: Recent advances in the genetics of spastic paraplegias.

  Giovanni Stevanin, Merle Ruberg, Alexis Brice
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  ABSTRACT: Hereditary spastic paraplegias (HSPs) are genetically heterogeneous mendelian disorders characterized by weakness and spasticity in the lower limbs associated with additional neurologic signs in "complex" or "complicated" forms. Major advances have been made during the past two decades in our understanding of their molecular bases. The mapping of 34 genes (17 of which have been identified) involved in this clinically diverse group of disorders has highlighted their great genetic heterogeneity. From the combined genetic and clinical information obtained, a new classification is now emerging that will help to better diagnose this condition, evaluate disease progression, guide follow-up, and permit genetic counselling. Evidence is now accumulating that at least part of the physiopathology results from abnormal intracellular trafficking, as well as from altered cell recognition and signaling, oligodendroglial dysfunction, mitochondrial defects, and impaired cholesterol and/or neurosteroid metabolism.
  Current Neurology and Neuroscience Reports 06/2008; 8(3):198-210. · 3.45 Impact Factor
• Article: Refinement of the 2p11.1-q12.2 locus responsible for cortical tremor associated with epilepsy and exclusion of candidate genes.

  Cécile Saint-Martin, Delphine Bouteiller, Giovanni Stevanin, Cyprian Popescu, Céline Charon, Merle Ruberg, Stéphanie Baulac, Eric LeGuern, Pierre Labauge, Christel Depienne
  Neurogenetics 03/2008; 9(1):69-71. · 3.35 Impact Factor
• Article: A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP.

  Christel Depienne, Estelle Fedirko, Jean-Marc Faucheux, Sylvie Forlani, Bernard Bricka, Cyril Goizet, Sylvie Lesourd, Giovanni Stevanin, Merle Ruberg, Alexandra Durr, Alexis Brice
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  ABSTRACT: SPG4/SPAST, the gene-encoding spastin, is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia (HSP). SPG4-HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation, especially regarding the severity and the age at onset. In this study, we investigated the origin of the mutation and the factors involved in intra-familial heterogeneity in a family with a SPG4 mutation. We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather, who was the only affected member of six siblings. His disease began at age 55, much later than in his daughter, who had onset at age 18, and his grandson, in whom onset was at age 5. These observations indicate that de novo mutations can occur in SPG4, and that somatic mosaicism might account for intra-familial variation in SPG4-linked HSP.
  Neurogenetics 09/2007; 8(3):231-3. · 3.35 Impact Factor
• Article: REM sleep behavior disorder in patients with guadeloupean parkinsonism, a tauopathy.

  Valérie Cochen De Cock, Annie Lannuzel, Stéphane Verhaeghe, Emmanuel Roze, Merle Ruberg, Jean Philippe Derenne, Jean Claude Willer, Marie Vidailhet, Isabelle Arnulf
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  ABSTRACT: To describe sleep characteristics and rapid eye movement (REM) sleep behavior disorder in patients with Guadeloupean atypical parkinsonism (Gd-PSP), a tauopathy resembling progressive supranuclear palsy that mainly affects the midbrain. It is possibly caused by the ingestion of sour sop (corossol), a tropical fruit containing acetogenins, which are mitochondrial poisons. Sleep interview, motor and cognitive tests, and overnight videopolysomnography. Thirty-six age-, sex-, disease-duration- and disability-matched patients with Gd-PSP (n = 9), progressive supranuclear palsy (a tauopathy, n = 9), Parkinson disease (a synucleinopathy, n = 9) and controls (n = 9). Tertiary-care academic hospital. REM sleep behavior disorder was found in 78% patients with Gd-PSP (43% of patients reported having this disorder several years before the onset of parkinsonism), 44% of patients with idiopathic Parkinson disease, 33% of patients with progressive supranuclear palsy, and no controls. The percentage of muscle activity during REM sleep was greater in patients with Gd-PSP than in controls (limb muscle activity, 8.3%+/-8.7% vs 0.1%+/- 0.2%; chin muscle activity, 24.3%+/- 23.7% vs 0.7%+/-2.0%) but similar to that of other patient groups. The latency and percentage of REM sleep were similar in patients with Gd-PSP, patients with Parkinson disease, and controls, whereas patients with progressive supranuclear palsy had delayed and shortened REM sleep. Although Gd-PSP is a tauopathy, most patients experience REM sleep behavior disorder. This suggests that the location of neuronal loss or dysfunction in the midbrain, rather than the protein comprising the histologic lesions (synuclein versus tau aggregation), is responsible for suppressing muscle atonia during REM sleep. Subjects with idiopathic REM sleep behavior disorder should avoid eating sour sop.
  Sleep 09/2007; 30(8):1026-32. · 5.05 Impact Factor
• Article: Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons.

  Myriam Escobar-Khondiker, Matthias Höllerhage, Marie-Paule Muriel, Pierre Champy, Antoine Bach, Christel Depienne, Gesine Respondek, Elizabeth S Yamada, Annie Lannuzel, Takao Yagi, Etienne C Hirsch, Wolfgang H Oertel, Ralf Jacob, Patrick P Michel, Merle Ruberg, Günter U Höglinger
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  ABSTRACT: A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibition, did not affect either the redistribution of tau or cell death. Both were prevented, however, by forced expression of the NDI1 nicotinamide adenine dinucleotide (NADH)-quinone-oxidoreductase of Saccharomyces cerevisiae, which can restore NADH oxidation in complex I-deficient mammalian cells and stimulation of energy production via anaerobic glycolysis. Consistently, other ATP-depleting neurotoxins (1-methyl-4-phenylpyridinium, 3-nitropropionic, and carbonyl cyanide m-chlorophenylhydrazone) reproduced the somatic redistribution of tau, whereas toxins that did not decrease ATP levels did not cause the redistribution of tau. Therefore, the annonacin-induced ATP depletion causes the retrograde transport of mitochondria to the cell soma and induces changes in the intracellular distribution of tau in a way that shares characteristics with some neurodegenerative diseases.
  Journal of Neuroscience 08/2007; 27(29):7827-37. · 7.11 Impact Factor
• Source

  Available from: Karim N'Diaye

  Article: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior.

  Luc Mallet, Michael Schüpbach, Karim N'Diaye, Philippe Remy, Eric Bardinet, Virginie Czernecki, Marie-Laure Welter, Antoine Pelissolo, Merle Ruberg, Yves Agid, Jérôme Yelnik
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  ABSTRACT: Two parkinsonian patients who experienced transient hypomanic states when the subthalamic nucleus (STN) was stimulated during postoperative adjustment of the electrical parameters for antiparkinsonian therapy agreed to have the mood disorder reproduced, in conjunction with motor, cognitive, and behavioral evaluations and concomitant functional neuroimaging. During the experiment, STN stimulation again induced a hypomanic state concomitant with activation of cortical and thalamic regions known to process limbic and associative information. This observation suggests that the STN plays a role in the control of a complex behavior that includes emotional as well as cognitive and motor components. The localization of the four contacts of the quadripolar electrode was determined precisely with an interactive brain atlas. The results showed that (i) the hypomanic state was caused only by stimulation through one contact localized in the anteromedial STN; (ii) both this contact and the contact immediately dorsal to it improved the parkinsonian motor state; (iii) the most dorsal and ventral contacts, located at the boundaries of the STN, neither induced the behavioral disorder nor improved motor performance. Detailed analysis of these data led us to consider a model in which the three functional modalities, emotional, cognitive, and motor, are not processed in a segregated manner but can be subtly combined in the small volume of the STN. This nucleus would thus serve as a nexus that integrates the motor, cognitive, and emotional components of behavior and might consequently be an effective target for the treatment of behavioral disorders that combine emotional, cognitive, and motor impairment.
  Proceedings of the National Academy of Sciences 07/2007; 104(25):10661-6. · 9.68 Impact Factor
• Article: Silencing of the Charcot-Marie-Tooth associated MTMR2 gene decreases proliferation and enhances cell death in primary cultures of Schwann cells.

  Alexandre Chojnowski, Nicole Ravisé, Corinne Bachelin, Christel Depienne, Merle Ruberg, Bernard Brugg, Jocelyn Laporte, Anne Baron-Van Evercooren, Eric LeGuern
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  ABSTRACT: Loss of function of the myotubularin (MTM)-related protein 2 (MTMR2) in Schwann cells causes Charcot-Marie-Tooth disease type 4B1, a severe demyelinating neuropathy, but the consequences of MTMR2 disruption in Schwann cells are unknown. We established the expression profile of MTMR2 by real-time RT-PCR during rat myelination and showed it to be preferentially expressed at the onset of the myelination period. We developed a model in which MTMR2 loss of function was reproduced in primary cultures of Schwann cells by RNA interference. We found that depletion of MTMR2 in Schwann cells decreased their rate of proliferation. Furthermore, when cultivated in serum-free medium, MTMR2 depletion increased the number of Schwann cells that died by a caspase-dependent process. These results support the hypothesis that loss of MTMR2 in patients, by decreasing Schwann cells proliferation and survival, may impair the first stages of myelination of the peripheral nervous system.
  Neurobiology of Disease 06/2007; 26(2):323-31. · 5.40 Impact Factor
• Article: Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia.

  Christel Depienne, Estelle Fedirko, Sylvie Forlani, Cécile Cazeneuve, Pascale Ribaï, Imed Feki, Chantal Tallaksen, Karine Nguyen, Bruno Stankoff, Merle Ruberg, Giovanni Stevanin, Alexandra Durr, Alexis Brice
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  ABSTRACT: Point mutations in SPG4, the gene encoding spastin, are a frequent cause of autosomal dominant hereditary spastic paraplegia (AD-HSP). However, standard methods for genetic analyses fail to detect exonic microdeletions. 121 mutation-negative probands were screened for rearrangements in SPG4 by multiplex ligation-dependent probe amplification. 24 patients with 16 different heterozygotic exon deletions in SPG4 (20%) were identified, ranging from one exon to the whole coding sequence. Comparison with 78 patients with point mutations showed a similar clinical picture but an earlier age at onset. Exon deletions in SPG4 are as frequent as point mutations, and SPG4 is responsible for 40% of AD-HSP.
  Journal of Medical Genetics 05/2007; 44(4):281-4. · 6.36 Impact Factor
• Article: A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes.

  Morwena Latouche, Christelle Lasbleiz, Elodie Martin, Véronique Monnier, Thomas Debeir, Annick Mouatt-Prigent, Marie-Paule Muriel, Lydie Morel, Merle Ruberg, Alexis Brice, Giovanni Stevanin, Hérvé Tricoire
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  ABSTRACT: Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin 7 (ATXN7) protein, a member of a multiprotein complex involved in histone acetylation. We have created a conditional Drosophila model of SCA7 in which expression of truncated ATXN7 (ATXN7T) with a pathogenic polyQ expansion is induced in neurons in adult flies. In this model, mutant ATXN7T accumulated in neuronal intranuclear inclusions containing ubiquitin, the 19S proteasome subunit, and HSP70 (heat shock protein 70), as in patients. Aggregation was accompanied by a decrease in locomotion and lifespan but limited neuronal death. Disaggregation of the inclusions, when expression of expanded ATXN7T was stopped, correlated with improved locomotor function and increased lifespan, suggesting that the pathology may respond to treatment. Lifespan was then used as a quantitative marker in a candidate gene approach to validate the interest of the model and to identify generic modulators of polyQ toxicity and specific modifiers of SCA7. Several molecular pathways identified in this focused screen (proteasome function, unfolded protein stress, caspase-dependent apoptosis, and histone acetylation) were further studied in primary neuronal cultures. Sodium butyrate, a histone deacetylase inhibitor, improved the survival time of the neurons. This model is therefore a powerful tool for studying SCA7 and for the development of potential therapies for polyQ diseases.
  Journal of Neuroscience 04/2007; 27(10):2483-92. · 7.11 Impact Factor