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30 results on '"Dürr, Alexandra"'

1. Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice

Author

Fortier, Manon, Cauhapé, Margaux, Buono, Suzie, Becker, Julien, Menuet, Alexia, Branchu, Julien, Ricca, Ivana, Mero, Serena, Dorgham, Karim, El Hachimi, Khalid-Hamid, Dobrenis, Kostantin, Colsch, Benoit, Samaroo, Dominic, Devaux, Morgan, Durr, Alexandra, Stevanin, Giovanni, Santorelli, Filippo M., Colombo, Sophie, Cowling, Belinda, and Darios, Frédéric

Published
2024
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2. Motor neuron pathology in CANVAS due to RFC1 expansions

Author

Huin, Vincent, Coarelli, Giulia, Guemy, Clément, Boluda, Susana, Debs, Rabab, Mochel, Fanny, Stojkovic, Tanya, Grabli, David, Maisonobe, Thierry, Gaymard, Bertrand, Lenglet, Timothée, Tard, Céline, Davion, Jean-Baptiste, Sablonnière, Bernard, Monin, Marie-Lorraine, Ewenczyk, Claire, Viala, Karine, Charles, Perrine, Ber, Isabelle Le, Reilly, Mary, Houlden, Henry, Cortese, Andrea, Seilhean, Danielle, Brice, Alexis, and Durr, Alexandra

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < .001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Published
2022
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3. CAG repeat mosaicism is gene specific in spinocerebellar ataxias

Author

Kacher, Radhia, Lejeune, François-Xavier, David, Isabelle, Boluda, Susana, Coarelli, Giulia, Leclere-Turbant, Sabrina, Heinzmann, Anna, Marelli, Cecilia, Charles, Perrine, Goizet, Cyril, Kabir, Nisha, Hilab, Rania, Jornea, Ludmila, Six, Julie, Dommergues, Marc, Fauret, Anne-Laure, Brice, Alexis, Humbert, Sandrine, and Durr, Alexandra

Published
2024
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5. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions

Author

Méreaux, Jean-Loup, Davoine, Claire-Sophie, Pellerin, David, Coarelli, Giulia, Coutelier, Marie, Ewenczyk, Claire, Monin, Marie-Lorraine, Anheim, Mathieu, Le Ber, Isabelle, Thobois, Stéphane, Gobert, Florent, Guillot-Noël, Léna, Forlani, Sylvie, Jornea, Ludmila, Heinzmann, Anna, Sangare, Aude, Gaymard, Bertrand, Guyant-Maréchal, Lucie, Charles, Perrine, Marelli, Cecilia, Honnorat, Jérôme, Degos, Bertrand, Tison, François, Sangla, Sophie, Simonetta-Moreau, Marion, Salachas, François, Tchikviladzé, Maya, Castelnovo, Giovanni, Mochel, Fanny, Klebe, Stephan, Castrioto, Anna, Fenu, Silvia, Méneret, Aurélie, Bourdain, Frédéric, Wandzel, Marion, Roth, Virginie, Bonnet, Céline, Riant, Florence, Stevanin, Giovanni, Noël, Sandrine, Fauret-Amsellem, Anne-Laure, Bahlo, Melanie, Lockhart, Paul J., Brais, Bernard, Renaud, Mathilde, Brice, Alexis, and Durr, Alexandra

Published
2024
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6. Individual perception of environmental factors that influence lower limbs spasticity in inherited spastic paraparesis

Author

Lallemant-Dudek, Pauline, MD, Parodi, Livia, PhD, Coarelli, Giulia, MD, Heinzmann, Anna, MD, Charles, Perrine, MD PhD, Ewenczyk, Claire, MD, PhD, Fenu, Silvia, MD, Monin, Marie-Lorraine, MD, Corcia, Philippe, MD PhD, Depienne, Christel, PhD, Mochel, Fanny, MD, PhD, Benard, Jean, PhD, Tezenas du Montcel, Sophie, MD, and Durr, Alexandra, MD, PhD

Published
2023
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8. Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias

Author

Cunha, Paulina, Petit, Emilien, Coutelier, Marie, Coarelli, Giulia, Mariotti, Caterina, Faber, Jennifer, Van Gaalen, Judith, Damasio, Joana, Fleszar, Zofia, Tosi, Michele, Rocca, Clarissa, De Michele, Giovanna, Minnerop, Martina, Ewenczyk, Claire, Santorelli, Filippo M., Heinzmann, Anna, Bird, Thomas, Amprosi, Matthias, Indelicato, Elisabetta, Benussi, Alberto, Charles, Perrine, Stendel, Claudia, Romano, Silvia, Scarlato, Marina, Le Ber, Isabelle, Bassi, Maria Teresa, Serrano, Mercedes, Schmitz-Hübsch, Tanja, Doss, Sarah, Van Velzen, Gijs A.J., Thomas, Quentin, Trabacca, Antonio, Ortigoza-Escobar, Juan Dario, D'Arrigo, Stefano, Timmann, Dagmar, Pantaleoni, Chiara, Martinuzzi, Andrea, Besse-Pinot, Elsa, Marsili, Luca, Cioffi, Ettore, Nicita, Francesco, Giorgetti, Alejandro, Moroni, Isabella, Romaniello, Romina, Casali, Carlo, Ponger, Penina, Casari, Giorgio, De Bot, Susanne T., Ristori, Giovanni, Blumkin, Lubov, Borroni, Barbara, Goizet, Cyril, Marelli, Cecilia, Boesch, Sylvia, Anheim, Mathieu, Filla, Alessandro, Houlden, Henry, Bertini, Enrico, Klopstock, Thomas, Synofzik, Matthis, Riant, Florence, Zanni, Ginevra, Magri, Stefania, Di Bella, Daniela, Nanetti, Lorenzo, Sequeiros, Jorge, Oliveira, Jorge, Van de Warrenburg, Bart, Schöls, Ludger, Taroni, Franco, Brice, Alexis, and Durr, Alexandra

Published
2023
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9. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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10. Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Author

Barbier, Mathieu, Davoine, Claire-Sophie, Petit, Emilien, Porché, Maximilien, Guillot-Noel, Léna, Sayah, Sabrina, Fauret, Anne-Laure, Neau, Jean-Philippe, Guyant-Maréchal, Lucie, Deffond, Didier, Tranchant, Christine, Goizet, Cyril, Coarelli, Giulia, Castrioto, Anna, Klebe, Stephan, Ewenczyk, Claire, Heinzmann, Anna, Charles, Perrine, Tchikviladzé, Maya, Van Broeckhoven, Christine, Brice, Alexis, and Durr, Alexandra

Published
2023
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11. Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Coarelli, Giulia, Heinzmann, Anna, Ewenczyk, Claire, Fischer, Clara, Chupin, Marie, Monin, Marie-Lorraine, Hurmic, Hortense, Calvas, Fabienne, Calvas, Patrick, Goizet, Cyril, Thobois, Stéphane, Anheim, Mathieu, Nguyen, Karine, Devos, David, Verny, Christophe, Ricigliano, Vito A G, Mangin, Jean-François, Brice, Alexis, Tezenas du Montcel, Sophie, and Durr, Alexandra

Published
2022
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12. Hedgerow structural diversity is key to promoting biodiversity and ecosystem services: A systematic review of Central European studies.

Author

Kratschmer, Sophie, Hauer, Julia, Zaller, Johann G., Dürr, Alexandra, and Weninger, Thomas

Subjects
WINDBREAKS, shelterbelts, etc., ANIMAL diversity, ECOSYSTEM services, BIODIVERSITY, SEED dispersal, SPECIES diversity, ECOSYSTEMS
Abstract

• Relations among hedgerow structure, biodiversity & ecosystem services are unclear. • We performed a systematic review including 89 studies from Central Europe and UK from 1974 to 2022. • Arthropods & birds, were most often, earthworms & bats least often studied. • Structural diversity, layering & woody vegetation promoted biodiversity. • Connectivity, density & structural complexity improved ecosystem service provision. Agricultural intensification decreases the heterogeneity of the landscape and leads to a decline in hedgerows. As hedgerows provide important habitats for many taxa, this contributes to the loss of biodiversity in agroecosystems. However, the extent to which hedgerows, and in particular their habitat quality in terms of structural characteristics, also influence biodiversity-based ecosystem services is poorly studied. Here, we conducted a systematic review of the Scopus and other literature databases focusing on Central European and UK studies examining (1) the influence of hedgerow habitat quality on the biodiversity of arthropods, earthworms, birds, bats and small mammals and (2) the relationship between selected hedgerow parameters, animal taxa, and ecosystem services such as pollination, seed dispersal, pest and disease control and soil quality regulation. A total of 2260 studies (cut-off date: 13 September 2022) published between 1974 and 2022 were found. After sorting based on inclusion criteria related to the research focus, 89 studies remained for evaluation. Arthropods, birds, and small mammals were studied most frequently, earthworms and bats least frequently. The selected studies showed that structural diversity, layering, woody biomass and density were strongly positively correlated with animal species diversity, while hedgerow length, width and age showed less relevant relationships. Hedgerow connectivity, density, structural diversity, and layering were strongly positive associated with the provision of ecosystem services. We conclude that the structural diversity of hedgerows needs to be increased if their impact on biodiversity and ecosystem service provision is to be improved. It is therefore recommended that hedgerow management measures should specifically consider the ecological importance of the structural diversity of hedgerows. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Hecken und ihre Ökosystemleistungen Einführung und Anwendung des Bewertungssystems Heck.in.

Author

Dürr, Alexandra, Weninger, Thomas, Loicht, Johanna, and Strauss, Peter

Abstract

In rural landscapes, hedgerows and windbreaks play a critical role in providing various ecosystem services. The functionality of these landscape elements depends on their structural characteristics and their placement in the landscape. Heck.in is a practically applicable evaluation system for hedgerows and windbreaks in cultural landscapes, based on scientific findings. It allows the quantification of ecosystem services. For this purpose, correlations between structural and site indicators with the provision of ecosystem services are described based on scientific findings and are summarized in a quantitative assessment scheme. By using Heck.in, an assessment of hedgerows can easily be carried out by both experts and non-specialists. The result is presented in the form of a graph and quantitative values covering 13 different ecosystem services. This allows identification of outstanding services as well as weak points in individual hedgerows, assessment of the impact of maintenance measures on functionality, and the making of comparisons. The scoring system was successfully tested in a regional study and proved to be practicable and differentiating. Future applications of Heck.in could be in planning processes, scientific studies, and educational campaigns for people of different ages and interest groups. [ABSTRACT FROM AUTHOR]

Published
2024
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17. PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

Author

Fevga, Christina, Tesson, Christelle, Carreras Mascaro, Ana, Courtin, Thomas, Van Coller, Riaan, Sakka, Salma, Ferraro, Federico, Farhat, Nouha, Bardien, Soraya, Damak, Mariem, Carr, Jonathan, Ferrien, Melanie, Boumeester, Valerie, Hundscheid, Jasmijn, Grillenzoni, Nicola, Kessissoglou, Irini A., Kuipers, Demy J.S., Quadri, Marialuisa, Agid, Yves, Anheim, Mathieu, Borg, Michel, Brice, Alexis, Broussolle, Emmanuel, Corvol, Jean Christophe, Damier, Philippe, Defebvre, Luc, Dürr, Alexandra, Durif, Franck, Houeto, Jean Luc, Krack, Paul, Klebe, Stephan, Lesage, Suzanne, Lohmann, Ebba, Martinez, Maria, Mangone, Graziella, Mariani, Louise Laure, Pollak, Pierre, Rascol, Olivier, Tison, François, Tranchant, Christine, Verin, Marc, Viallet, François, Vidailhet, Marie, Emre, Murat, Hanagasi, Hasmet, Bilgic, Basar, Lu, Bedia Marangozog, Benmahdjoub, Mustapha, Arezki, Mohammed, Bouchetara, Sofiane A., Benhassine, Traki, Tazir, Meriem, Djebara, Mouna Ben, Gouider, Riadh, Romdhan, Sawssan Ben, Mhiri, Chokri, Bouhouche, Ahmed, Bonifati, Vincenzo, Mandemakers, Wim, Kievit, Anneke J.A., Boon, Agnita J.W., Ferreira, Joaquim J., Guedes, Leonor Correia, Hanagasi, Hasmet A., Tufekcioglu, Zeynep, Elibol, Bulent, Dog.u, Okan, Gultekin, Murat, Chien, Hsin F., Barbosa, Egberto, Jardim, Laura Bannach, Rieder, Carlos R.M., Chang, Hsiu Chen, Lu, Chin Song, Wu-Chou, Yah Huei, Yeh, Tu Hsueh, Lopiano, Leonardo, Tassorelli, Cristina, Pacchetti, Claudio, Comi, Cristoforo, Raudino, Francesco, Bertolasi, Laura, Tinazzi, Michele, Bonizzato, Alberto, Ferracci, Carlo, Marconi, Roberto, Guidi, Marco, Onofrj, Marco, Thomas, Astrid, Vanacore, Nicola, Meco, Giuseppe, Fabrizio, Edito, Fabbrini, Giovanni, Berardelli, Alfredo, Stocchi, Fabrizio, Vacca, Laura, Barone, Paolo, Picillo, Marina, De Michele, Giuseppe, Criscuolo, Chiara, De Mari, Michele, Dell'aquila, Claudia, Iliceto, Giovanni, Toni, Vincenzo, Trianni, Giorgio, Saddi, Valeria, Cossu, Gianni, Melis, Maurizio, Hassan, Bassem A., Breedveld, Guido J., Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Faculty of Health Sciences [Pretoria], University of Pretoria [South Africa], Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Stellenbosch University, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Motivation, cerveau et comportement = Motivation, Brain and Behavior [ICM Paris] (MBB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Tesson, Christelle, Clinical Genetics, and Neurology

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, PTPA, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PPP2R4, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, parkinsonism, PP2A
Abstract

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Published
2023

19. Genome-wide association study identifies a new susceptibility locus inPLA2G4Cfor Multiple System Atrophy

Author

Nakahara, Yasuo, primary, Mitsui, Jun, additional, Date, Hidetoshi, additional, Porto, Kristine Joyce, additional, Hayashi, Yasuhiro, additional, Yamashita, Atsushi, additional, Kusakabe, Yoshio, additional, Matsukawa, Takashi, additional, Ishiura, Hiroyuki, additional, Yasuda, Tsutomu, additional, Iwata, Atsushi, additional, Goto, Jun, additional, Ichikawa, Yaeko, additional, Momose, Yoshio, additional, Takahashi, Yuji, additional, Toda, Tatsushi, additional, Ohta, Rikifumi, additional, Yoshimura, Jun, additional, Morishita, Shinichi, additional, Gustavsson, Emil K, additional, Christy, Darren, additional, Maczis, Melissa, additional, Farrer, Matthew J., additional, Kim, Han-Joon, additional, Park, Sung-Sup, additional, Jeon, Beomseok, additional, Zhang, Jin, additional, Gu, Weihong, additional, Scholz, Sonja W., additional, Singleton, Andrew B., additional, Houlden, Henry, additional, Yabe, Ichiro, additional, Sasaki, Hidenao, additional, Matsushima, Masaaki, additional, Takashima, Hiroshi, additional, Kikuchi, Akio, additional, Aoki, Masashi, additional, Hara, Kenju, additional, Kakita, Akiyoshi, additional, Yamada, Mitsunori, additional, Takahashi, Hitoshi, additional, Onodera, Osamu, additional, Nishizawa, Masatoyo, additional, Watanabe, Hirohisa, additional, Ito, Mizuki, additional, Sobue, Gen, additional, Ishikawa, Kinya, additional, Mizusawa, Hidehiro, additional, Kanai, Kazuaki, additional, Kuwabara, Satoshi, additional, Arai, Kimihito, additional, Koyano, Shigeru, additional, Kuroiwa, Yoshiyuki, additional, Hasegawa, Kazuko, additional, Yuasa, Tatsuhiko, additional, Yasui, Kenichi, additional, Nakashima, Kenji, additional, Ito, Hijiri, additional, Izumi, Yuishin, additional, Kaji, Ryuji, additional, Kato, Takeo, additional, Kusunoki, Susumu, additional, Osaki, Yasushi, additional, Horiuchi, Masahiro, additional, Yamamoto, Ken, additional, Shimada, Mihoko, additional, Miyagawa, Taku, additional, Kawai, Yosuke, additional, Nishida, Nao, additional, Tokunaga, Katsushi, additional, Dürr, Alexandra, additional, Brice, Alexis, additional, Filla, Alessandro, additional, Klockgether, Thomas, additional, Wüllner, Ullrich, additional, Tanner, Caroline M., additional, Kukull, Walter A., additional, Lee, Virginia M.-Y., additional, Masliah, Eliezer, additional, Low, Phillip A., additional, Sandroni, Paola, additional, Ozelius, Laurie, additional, Foroud, Tatiana, additional, and Tsuji, Shoji, additional

Published
2023
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20. Heck.in. Hecken und ihre Ökosystemleistungen - eine Bewertung anhand von Indikatoren

Author

Dürr Alexandra, Loicht Johanna, Strauss Peter, Hösl Rosemarie, and Weninger Thomas

Subjects
Windbreak, Hedgerow, Soil Protection, Landscape Ecology, Ecosystem Services, Ecological Assessment
Abstract

Structural elements in rural landscapes, such as hedgerows and windbreaks, provide a range of ecosystem services.The potential for their functionality is determined by structural characteristics and placement in the landscape.Heck.in is a scientifically based and ready-to-use assessment system for hedgerows or windbreaks in rural landscapes that quantifies the fulfillment of ecosystem services. The relationships between structural and locational indicators with ecosystem service delivery have been described based on results from scientific work around the world and combined into a quantitative assessment scheme. With this scheme a hedgerow can be easily evaluated by interested laymen, as a result a classification of 13 different ecosystem services is given in graphical and quantitative form. On this basis, particularly pronounced services or weak points of individual hedges can be made visible, the impact of maintenance measures on functionality can be estimated and comparisons can be made. The application can be made in scientific studies, planning procedures or in the context of training campaigns with all age and interest groups. ZIP-Package contains: - Manual and project description - long version (100 p) - Technical manual for field assessment (24 p) - Form for hedgerow assessment - Model file for hedgerow assessment ************************************************************************************************************************************* Strukturelemente in ländlichen Landschaften, wie Hecken und Windschutzstreifen, erfüllen eine Reihe von Ökosystemleistungen.Das Potenzial für ihre Funktionalität wird durch strukturelle Eigenschaften und die Anordnung in der Landschaft bestimmt.Heck.in ist ein wissenschaftlich fundiertes und anwendungsbereites Bewertungssystem für Hecken oder Windschutzstreifen in ländlichen Landschaften, das die Erfüllung von Ökosystemleistungen quantifiziert. Die Zusammenhänge zwischen strukturellen und Lageindikatoren mit der Erbringung von Ökosystemleistungen wurden auf der Basis von Ergebnissen aus wissenschaftlichen Arbeiten aus aller Welt beschrieben und in einem quantitativen Bewertungsschema zusammengeführt. Mit diesem Schema kann eine Hecke von interessierten Laien einfach bewertet werden, als Ergebnis wird eine Klassifizierung von 13 verschiedenen Ökosystemleistungen in graphischer und quantitativer Form ausgegeben. Auf dieser Basis können besonders ausgeprägte Leistungen oder Schwachpunkte einzelner Hecken sichtbar gemacht werden, die Auswirkung von Pflegemaßnahmen auf die Funktionalität abgeschätzt werden und Vergleiche können gezogen werden. Die Anwendung kann in wissenschaftlichen Studien, Planungsverfahren oder im Rahmen von Schulungsaktionen mit allen Alters- und Interessensgruppen erfolgen. ZIP-Package beinhaltet: - Manual und Projektbeschreibung - Langfassung(100 p) - Kurzfassung /Kartieranleitung(24 p) - Formular für Heckenbewertung - Eingabe- und Berechnungsdatei mit Bewertungsmodell

Published
2023
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21. De Novo and Dominantly Inherited <scp> SPTAN1 </scp> Mutations Cause Spastic Paraplegia and Cerebellar Ataxia

Author

Van de Vondel, Liedewei, De Winter, Jonathan, Deconinck, Tine, Vural, Atay, Ertan, Sibel, Dogu, Okan, Uysal, Hilmi, Brankovic, Vesna, Herzog, Rebecca, Brice, Alexis, Dürr, Alexandra, Klebe, Stephan, Beijer, Danique, Stock, Friedrich, Bischoff, Almut Turid, Rattay, Tim W, Sobrido, María-Jesús, De Michele, Giovanna, De Jonghe, Peter, Klopstock, Thomas, Lohmann, Katja, Zanni, Ginevra, Santorelli, Filippo M, Coarelli, Giulia, Timmerman, Vincent, Haack, Tobias B, Züchner, Stephan, Consortium, PREPARE, Schüle, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Basak, A Nazli, Baets, Jonathan, Wayand, Melanie, Palvadeau, Robin, Pauly, Martje G, Klein, Katrin, Rautenberg, Maren, Guillot-Noël, Léna, and PREPARE Consortium

Subjects
spastic paraplegia, Cerebellar Ataxia, genetics [Spectrin], Medizin, genetics [Mutation], genetics [Carrier Proteins], Article, genetics [Paraplegia], genetics [Spastic Paraplegia, Hereditary], Intellectual Disability, Humans, ddc:610, Paraplegia, genetics [Cerebellar Ataxia], Spastic Paraplegia, Hereditary, ataxia, Microfilament Proteins, rare diseases, Spectrin, Pedigree, spectrin, Phenotype, Neurology, Mutation, next-generation sequencing, Human medicine, Neurology (clinical), genetics [Intellectual Disability], genetics [Microfilament Proteins], Carrier Proteins
Abstract

Background Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. Objectives We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. Methods We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. Results We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. Conclusions We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society

Published
2022

22. Differences in Survival across Monogenic Forms of Parkinson's Disease.

Author

Lanore, Aymeric, Casse, Fanny, Tesson, Christelle, Courtin, Thomas, Menon, Poornima Jayadev, Sambin, Sara, Mangone, Graziella, Mariani, Louise‐Laure, Lesage, Suzanne, Brice, Alexis, Elbaz, Alexis, Corvol, Jean‐Christophe, Agid, Yves, Anheim, Mathieu, Borg, Michel, Broussolle, Emmanuel, Damier, Philippe, Defebvre, Luc, Dürr, Alexandra, and Durif, Franck

Subjects
PARKINSON'S disease, GENETIC counseling, DARDARIN, OVERALL survival, VITAL records (Births, deaths, etc.), MOVEMENT disorders
Abstract

Objective: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. Methods: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. Results: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow‐up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. Interpretation: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123–132 [ABSTRACT FROM AUTHOR]

Published
2023
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23. Ökologische Bewertung von niederösterreichischen Hecken: Vergleich zweier Methoden

Author

Dürr, Alexandra

Abstract

Hecken sind wichtige Bestandteile von Kulturlandschaften weltweit. Sie erbringen eine Vielzahl an Ökosystemleistungen (ÖSL). Jedoch erbringt nicht jede Hecke diese Leistungen in gleichem Maße. Das Heck.in Bewertungsschema wurde entwi-ckelt, um den Erfüllungsgrad verschiedener ÖSL einer Hecke zu erfassen. Hierfür wird auf möglichst einfach zu erfassende Indikatoren zurückgegriffen. Ziel dieser Arbeit ist die Evaluierung eines Teils dieses Schemas – die Bewertung der Habitatleistungen (Nahrungsquelle, Korridor, Ruhe- und Fortpflanzungsstät-te). Hierfür wurden fünfzig niederösterreichische Hecken mit dem Schema aufge-nommen und bewertet. Die Ergebnisse wurden dann mit einer parallel dazu erho-benen Biotopbewertung verglichen. Zudem wurde der qualitative Zustand der un-tersuchten Hecken beleuchtet. Die Mittelwerte der Ergebnisse beider Bewertungsmethoden sind nahezu iden-tisch, Differenzen bestehen jedoch in der Verteilung der Ergebnisse. Abweichun-gen könnten auf methodische Unterschiede zurückzuführen sein, z.B. eine abstu-fende Bewertung in Heck.in vs. Ja-/Nein-Entscheidungen in der Biotopbewer-tung. Auch die verschiedenen Blickwinkel (Heck.in: tierökologisch, Biotopbewer-tung: botanisch) und der Einfluss der Korridorleistung könnten Gründe sein. Die Qualität der Habitatleistungen der untersuchten Hecken unterscheidet sich zwischen Hecken aus traditionellen Heckenlandschaften und seit 1970 angelegten Bodenschutzanlagen in den ÖSL Nahrungsquellen und Ruhe- und Fortpflanzungs-stätte, sowie in den Gesamt-Habitatleistungen signifikant. Lediglich die Korri-dorleistung wird in beiden Gruppen gleichermaßen erbracht. Die insgesamt am schlechtesten bewerteten Indikatoren sind: Saum, Totholz, Heckendichte und Netzwerk. Sie bieten damit das größte Verbesserungspotenzial. Für ‚Saum‘ und ‚Totholz‘ sind verbesserte Managementpraktiken an der Einzelhecke nötig, für ‚Heckendichte‘ und ‚Netzwerk‘ ist eine großräumigere Planung notwendig., Hedgerows are important components of cultural landscapes worldwide and pro-vide a variety of ecosystem services (ESS). However, not every hedgerow provides these services to the same extent. The Heck.in assessment scheme was developed to rate the degree to which each hedgerow fulfills different ESS of a hedgerow by relying on easy-recordable indicators. The aim of this thesis is to evaluate one part of this scheme – the assessment of habitat services (food source, corridor, resting and breeding site). To this end, fif-ty hedges in Lower Austria were recorded and evaluated with the scheme. The re-sults were then compared to a biotope assessment made at the same time. Fur-thermore, the qualitative condition of the examined hedgerows was analyzed. The mean values of the results of both assessment methods are almost identical, but a difference was found in the distribution of the results. Discrepancies could be due to methodological differences, for example graded scoring in Heck.in vs. yes/no decisions in the biotope assessment. The different perspectives (Heck.in: faunistic, biotope assessment: botanical) and the influence of corridor perfor-mance could also be reasons. The quality of habitat services of the studied hedgerows differs significantly be-tween hedgerows in traditional hedgerow landscapes and shelter belts established since 1970 in the ESS food source and resting and breeding sites, as well as in the overall habitat services. Only the ESS corridor are equally performed in both groups. The lowest scoring indicators overall are: Margin, deadwood, hedgerow density, and network. They therefore offer the greatest potential for improve-ment. For the indicators margin and deadwood, improved management practices are needed at the single hedge, and for hedge density and network, more large-scale planning is needed.

Published
2022
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25. SCA27B/FGF14 : une ataxie peut en cacher une autre

Author

Méreaux, Jean-Loup, Davoine, Claire-Sophie, Pellerin, David, Coarelli, Giulia, Renaud, Mathilde, Brice, Alexis, and Dürr, Alexandra

Abstract

Une expansion intronique GAA≥250 dans le gène FGF14 cause l’ataxie cérébelleuse autosomique dominante SCA27B et rejoint les 15 autres ataxies cérébelleuses dues à des expansions de motifs répétés.

Published
2024
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26. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire-Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergem, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Darios, Frédéric, Forlani, Sylvie, Site, Pitié-Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Fontaine, Bertrand, Azulay, Jean-Philippe, Boesfplug-Tanguy, Odile, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Laura, Jardim, Guergueltcheva, Velina, Tournev, Ivalo, Pedraza Linarès, Olga Lucia, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Lossos, Alexander, Bassi, Maria-Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Kremer, Berry, Van Roon-Mom, Willeke, Roxburgh, Richard, Erichsen, Anne Kjersti, Tallaksen, Chantal, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S, Rouco Axpe, Idoia, Elsayed, Liena, Paucar, Martin Arce, Roumani, Samir, Bing-Wen, Soong, Reid, Evan, Suran, Nethisinghe, Warner, Thomas, and Wood, Nicholas

Published
2021
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28. Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.

Author

Nakahara Y, Mitsui J, Date H, Porto KJ, Hayashi Y, Yamashita A, Kusakabe Y, Matsukawa T, Ishiura H, Yasuda T, Iwata A, Goto J, Ichikawa Y, Momose Y, Takahashi Y, Toda T, Ohta R, Yoshimura J, Morishita S, Gustavsson EK, Christy D, Maczis M, Farrer MJ, Kim HJ, Park SS, Jeon B, Zhang J, Gu W, Scholz SW, Singleton AB, Houlden H, Yabe I, Sasaki H, Matsushima M, Takashima H, Kikuchi A, Aoki M, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Yamamoto K, Shimada M, Miyagawa T, Kawai Y, Nishida N, Tokunaga K, Dürr A, Brice A, Filla A, Klockgether T, Wüllner U, Tanner CM, Kukull WA, Lee VM, Masliah E, Low PA, Sandroni P, Ozelius L, Foroud T, and Tsuji S

Abstract

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

Published
2023
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29. Haplotyping SNPs for allele-specific gene editing of the expanded huntingtin allele using long-read sequencing.

Author

Fang L, Monteys AM, Dürr A, Keiser M, Cheng C, Harapanahalli A, Gonzalez-Alegre P, Davidson BL, and Wang K

Subjects
Humans, Alleles, Polymorphism, Single Nucleotide genetics, Haplotypes genetics, Gene Editing, Neurodegenerative Diseases
Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG trinucleotide repeat expansions in exon-1 of huntingtin ( HTT ). Currently, there is no cure for HD, and the clinical care of individuals with HD is focused on symptom management. Previously, we showed allele-specific deletion of the expanded HTT allele ( mHTT) using CRISPR-Cas9 by targeting nearby (<10 kb) SNPs that created or eliminated a protospacer adjacent motif (PAM) near exon-1. Here, we comprehensively analyzed all potential PAM sites within a 10.4-kb genomic region flanking exon-1 of HTT in 983 individuals with HD using a multiplex targeted long-read sequencing approach on the Oxford Nanopore platform. We developed computational tools (NanoBinner and NanoRepeat) to de-multiplex the data, detect repeats, and phase the reads on the expanded or the wild-type HTT allele. One SNP common to 30% of individuals with HD of European ancestry emerged through this analysis, which was confirmed as a strong candidate for allele-specific deletion of the mHTT in human HD cell lines. In addition, up to 57% HD individuals may be candidates for allele-specific editing through combinatorial SNP targeting. Cumulatively, we provide a haplotype map of the region surrounding exon-1 of HTT in individuals affected with HD. Our workflow can be applied to other repeat expansion diseases to facilitate the design of guide RNAs for allele-specific gene editing., Competing Interests: P.G.-A. is currently employed by Spark Therapeutics., (© 2022 The Author(s).)

Published
2022
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30. Preparation of a stable CCL5·CCR5·G i signaling complex for Cryo-EM analysis.

Author

Isaikina P, Tsai CJ, Petrovic I, Rogowski M, Dürr AM, and Grzesiek S

Subjects
Chemokine CCL5 chemistry, Chemokines metabolism, Cryoelectron Microscopy, Humans, Receptors, G-Protein-Coupled, Receptors, CCR5 chemistry, Receptors, CCR5 metabolism, Signal Transduction
Abstract

The numerous chemokines and their cognate G protein-coupled chemokine receptors on the surface of leukocytes form a complex signaling network, which regulates the immune response and also other key physiological processes. Currently only a very limited number of structures of chemokine•chemokine receptor complexes have been solved. More structures are needed for the understanding of their mechanism of action and the rational design of drugs against these highly relevant therapeutic targets. Recently, we have determined the cryo-EM structure of the human wild-type CCR5 chemokine receptor, which is also the HIV-1 coreceptor, in its active conformation bound to the chemokine super-agonist [6P4]CCL5 and the heterotrimeric G i protein. The structure provides the rationale for the sequence-activity relation of agonist and antagonist CCR5 chemokine ligands. In this chapter, we present a detailed protocol for the preparation of the active agonist chemokine•CCR5•G i complex for cryo-EM studies including quality controls and caveats. As such the protocol may serve as starting point for structural and biophysical studies of other chemokine•chemokine receptor complexes., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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