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1. Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Author

Früh, Simon, Boudkkazi, Sami, Koppensteiner, Peter, Sereikaite, Vita, Chen, Li-Yuan, Fernandez-Fernandez, Diego, Rem, Pascal, Ulrich, Daniel, Schwenk, Jochen, Chen, Ziyang, Le Monnier, Elodie, Fritzius, Thorsten, Innocenti, Sabrina, Besseyrias, Valérie, Trovò, Luca, Stawarski, Michal, Argilli, Emanuela, Sherr, Elliott, van Bon, Bregje, Kamsteeg, Erik-Jan, Iascone, Maria, Pilotta, Alba, Cutrì, Maria, Azamian, Mahshid, Hernández-García, Andrés, Lalani, Seema, Rosenfeld, Jill, Zhao, Xiaonan, Vogel, Tiphanie, Ona, Herda, Scott, Daryl, Scheiffele, Peter, Strømgaard, Kristian, Tafti, Mehdi, Gassmann, Martin, Fakler, Bernd, Shigemoto, Ryuichi, and Bettler, Bernhard

Subjects
Animals, Female, Humans, Male, Mice, Alleles, Epilepsy, Loss of Function Mutation, Mice, Knockout, Neurodevelopmental Disorders, Neuronal Plasticity, Neurons, Neurotransmitter Agents, Synapses, Synaptic Transmission, Cell Adhesion Molecules
Abstract

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Published
2024

4. Multidimensional item Response theory to assess the psychometric properties of persian version of dutch eating behavior questionnaire (DEBQ) in university students

Author

Doostfatemeh, Marziyeh, Haem, Elham, Sarbaraninan, Mohadeseh, and Ajdari Tafti, Mehdi

Subjects
College students -- Food and nutrition -- Testing -- Psychological aspects, Psychological tests -- Evaluation, Food habits -- Diagnosis, Psychology and mental health
Abstract

The Multidimensional item response theory (MIRT) is a powerful modeling approach which could provide an ideal foundation for health psychologists to improve their survey-development and assessment. The current study aimed to illustrate the advantages of applying the MIRT models in investigating psychometric quality of the Dutch Eating Behavior Questionnaire (DEBQ). The Persian version of DEBQ questionnaire was administered to a sample of 509 Iranian university students. The three-factor MIRT model was applied to model the observed scores for each item of the DEBQ as a probability function of the individual's latent traits (here eating behaviors) while taking the correlation among questionnaire's dimensions into account. Strength of fit of MIRT model was reported based on multiple indices and individual items were illustrate in detail through item characteristic curves. Item information curves were also described the amount of information carried by different items. The goodness of fit indices which extracted from the result of MIRT model indicated acceptable structural validity of DEBQ with three factor to support for the dominant three-dimensional structure. Item discrimination parameters ranged from 0.56 to 3.39, 0.77 to 3.56 and 0.67 to 2.14 for restrained eating, emotional eating, and external eating, respectively. Moreover, items 4, item 23 and item 30 provided the least information in restrained, emotional, and external eating subscales., Author(s): Marziyeh Doostfatemeh [sup.1] , Elham Haem [sup.1] , Mohadeseh Sarbaraninan [sup.1] , Mehdi Ajdari Tafti [sup.2] Author Affiliations: (1) grid.412571.4, 0000 0000 8819 4698, Department of Biostatistics, Medical School, [...]

Published
2023
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5. Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea–related Quantitative Trait Locus in Men

Author

Chen, Han, Cade, Brian E, Gleason, Kevin J, Bjonnes, Andrew C, Stilp, Adrienne M, Sofer, Tamar, Conomos, Matthew P, Ancoli-Israel, Sonia, Arens, Raanan, Azarbarzin, Ali, Bell, Graeme I, Below, Jennifer E, Chun, Sung, Evans, Daniel S, Ewert, Ralf, Frazier-Wood, Alexis C, Gharib, Sina A, Haba-Rubio, José, Hagen, Erika W, Heinzer, Raphael, Hillman, David R, Johnson, W Craig, Kutalik, Zoltan, Lane, Jacqueline M, Larkin, Emma K, Lee, Seung Ku, Liang, Jingjing, Loredo, Jose S, Mukherjee, Sutapa, Palmer, Lyle J, Papanicolaou, George J, Penzel, Thomas, Peppard, Paul E, Post, Wendy S, Ramos, Alberto R, Rice, Ken, Rotter, Jerome I, Sands, Scott A, Shah, Neomi A, Shin, Chol, Stone, Katie L, Stubbe, Beate, Sul, Jae Hoon, Tafti, Mehdi, Taylor, Kent D, Teumer, Alexander, Thornton, Timothy A, Tranah, Gregory J, Wang, Chaolong, Wang, Heming, Warby, Simon C, Wellman, D Andrew, Zee, Phyllis C, Hanis, Craig L, Laurie, Cathy C, Gottlieb, Daniel J, Patel, Sanjay R, Zhu, Xiaofeng, Sunyaev, Shamil R, Saxena, Richa, Lin, Xihong, and Redline, Susan

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Sleep Research, Clinical Research, Human Genome, Lung, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Phosphatidylethanolamine N-Methyltransferase, Quantitative Trait Loci, Sex Characteristics, Sleep Apnea, Obstructive, Sleep, REM, Sterol Regulatory Element Binding Protein 1, Trans-Activators, Transcription Factors, ras Proteins, obstructive sleep apnea, genetics, genome-wide association studies, multiethnic, sexual dimorphism, Cardiorespiratory Medicine and Haematology, Respiratory System, Biochemistry and cell biology, Cardiovascular medicine and haematology
Abstract

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

Published
2018

15. Sleep modulates haematopoiesis and protects against atherosclerosis

Author

McAlpine, Cameron S., Kiss, Máté G., Rattik, Sara, He, Shun, Vassalli, Anne, Valet, Colin, Anzai, Atsushi, Chan, Christopher T., Mindur, John E., Kahles, Florian, Poller, Wolfram C., Frodermann, Vanessa, Fenn, Ashley M., Gregory, Annemijn F., Halle, Lennard, Iwamoto, Yoshiko, Hoyer, Friedrich F., Binder, Christoph J., Libby, Peter, Tafti, Mehdi, Scammell, Thomas E., Nahrendorf, Matthias, and Swirski, Filip K.

Published
2019
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17. Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

Author

Seifinejad, Ali, primary, Ramosaj, Mergim, additional, Shan, Ling, additional, Li, Sha, additional, Possovre, Marie-Laure, additional, Pfister, Corinne, additional, Fronczek, Rolf, additional, Garrett-Sinha, Lee A., additional, Frieser, David, additional, Honda, Makoto, additional, Arribat, Yoan, additional, Grepper, Dogan, additional, Amati, Francesca, additional, Picot, Marie, additional, Agnoletto, Andrea, additional, Iseli, Christian, additional, Chartrel, Nicolas, additional, Liblau, Roland, additional, Lammers, Gert J., additional, Vassalli, Anne, additional, and Tafti, Mehdi, additional

Published
2023
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18. Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

Author

Seifinejad, Ali, Ramosaj, Mergim, Shan, Ling, Li, Sha, Possovre, Marie-Laure, Pfister, Corinne, Fronczek, Rolf, Garrett-Sinha, Lee A, Frieser, David, Honda, Makoto, Arribat, Yoan, Grepper, Dogan, Amati, Francesca, Picot, Marie, Agnoletto, Andrea, Iseli, Christian, Chartrel, Nicolas, Liblau, Roland, Lammers, Gert J, Vassalli, Anne, Tafti, Mehdi, Seifinejad, Ali, Ramosaj, Mergim, Shan, Ling, Li, Sha, Possovre, Marie-Laure, Pfister, Corinne, Fronczek, Rolf, Garrett-Sinha, Lee A, Frieser, David, Honda, Makoto, Arribat, Yoan, Grepper, Dogan, Amati, Francesca, Picot, Marie, Agnoletto, Andrea, Iseli, Christian, Chartrel, Nicolas, Liblau, Roland, Lammers, Gert J, Vassalli, Anne, and Tafti, Mehdi

Abstract

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

Published
2023

25. Contributors

Author

Abbott, Sabra M., primary, Achermann, Peter, additional, Ainslie, Philip N., additional, Åkerstedt, Torbjörn, additional, Allada, Ravi, additional, Allen, Richard P., additional, Almeida, Fernanda R., additional, Amara, Amy W., additional, Ancoli-Israel, Sonia, additional, Angel, Chelsea, additional, Arima, Taro, additional, Arnedt, J. Todd, additional, Arnulf, Isabelle, additional, Avidan, Alon Y., additional, Axelsson, John, additional, Badr, M. Safwan, additional, Baghdoyan, Helen A., additional, Baker, Fiona C., additional, Balkin, Thomas J., additional, Balserak, Bilgay Izci, additional, Banks, Siobhan, additional, Barczi, Steven R., additional, Basner, Mathias, additional, Bassetti, Claudio L., additional, Baumann, Christian R., additional, Bazalakova, Mihaela, additional, Beaulieu-Bonneau, Simon, additional, Belenky, Gregory, additional, Benca, Ruth M., additional, Benson, Kathleen L., additional, Berger, Mark B., additional, Berry, Richard B., additional, Bliwise, Donald L., additional, Boeve, Bradley F., additional, Borbély, Alexander A., additional, Brown, Daniel B., additional, Buenaver, Luis, additional, Burgess, Keith R., additional, Butler, Jane E., additional, Buxton, Orfeu M., additional, Buysse, Daniel J., additional, Byrne, Enda M., additional, Cao, Michelle T., additional, Carney, Colleen E., additional, Carr, Michelle, additional, Carra, Maria Clotilde, additional, Carrizo, Santiago J., additional, Carskadon, Mary A., additional, Castrillon, Eduardo, additional, Challet, Etienne, additional, Chervin, Ronald D., additional, Cistulli, Peter A., additional, Cortese, Samuele, additional, Courcoulas, Anita P., additional, Craft, Robert, additional, Cramer, Michel A., additional, Culebras, Antonio, additional, Czeisler, Charles A., additional, Czisch, Michael, additional, Dauvilliers, Yves, additional, Davidson, Judith R., additional, D'Cruz, O'Neill F., additional, Deboer, Tom, additional, Gennaro, Luigi De, additional, Dement, William C., additional, Dempsey, Jerome A., additional, Dijk, Derk-Jan, additional, Dinges, David F., additional, Domhoff, G. William, additional, Dorrian, Jill, additional, Doufas, Anthony G., additional, Drager, Luciano F., additional, Drake, Christopher L., additional, Dresler, Martin, additional, Eastwood, Peter R., additional, Eckert, Danny J., additional, Edinger, Jack D., additional, Ellis, Jason Gordon, additional, Ely, E. Wesley, additional, Erlacher, Daniel, additional, Essick, Gregory K., additional, Facco, Francesca, additional, Farshidpanah, Siavash, additional, Feinberg, Irwin, additional, Ferini-Strambi, Luigi, additional, Fernandez-Mendoza, Julio, additional, Ferrara, Michele, additional, Ferri, Raffaele, additional, Fogel, Stuart, additional, Franken, Paul, additional, Franklin, Karl A., additional, Freedman, Neil, additional, Fulda, Stephany, additional, Gabehart, Rylie J., additional, Gamaldo, Charlene E., additional, Gander, Philippa H., additional, Gehrman, Philip R., additional, Gold, Avram R., additional, Goldstein, Cathy A., additional, Gooley, Joshua J., additional, Gosselin, Nadia, additional, Greenberg, Harly, additional, Grosbellet, Edith, additional, Grote, Ludger, additional, Guilleminault, Christian, additional, Gulyani, Seema, additional, Hall, Martica H., additional, Harper, Ronald M., additional, Harvey, Allison G., additional, Hedner, Jan, additional, Heinzer, Raphael, additional, Herman, John H., additional, Hillman, David R., additional, Hirshkowitz, Max, additional, Hoeg, Laura, additional, Hoekema, Aarnoud, additional, Högl, Birgit, additional, Hor, Hyun, additional, Horner, Richard L., additional, Hursh, Steven R., additional, Huynh, Nelly, additional, Ioachimescu, Adriana G., additional, Ioachimescu, Octavian C., additional, Sau-Man Ip, Mary, additional, Iranzo, Alex, additional, Javaheri, Shahrokh, additional, Jiang, Peng, additional, Joffe, Hadine, additional, Josephson, Mark E., additional, Kales, Stefanos N., additional, Katz, Eliot S., additional, Kecklund, Göran, additional, Keenan, Brendan T., additional, Keenan, Sharon, additional, Keifer, John C., additional, Kilduff, Thomas S., additional, Kirsch, Douglas, additional, Kline, Christopher E., additional, Kloss, Jacqueline DeMichele, additional, Knauert, Melissa Pauline, additional, Kothare, Sanjeev V., additional, Koyano, Kiyoshi, additional, Kräuchi, Kurt, additional, Krueger, James M., additional, Kryger, Meir, additional, Krystal, Andrew D., additional, Kutscher, Scott J., additional, Kwan, Anthony B., additional, Lakticova, Viera, additional, Lamp, Amanda, additional, Landolt, Hans-Peter, additional, Lanfranchi, Paola A., additional, Lavigne, Gilles, additional, Lecendreux, Michel, additional, Lee, Kathryn Aldrich, additional, Leggett, Melanie K., additional, Lettieri, Christopher J., additional, Lichstein, Kenneth L., additional, Lobbezoo, Frank, additional, Lorenzi-Filho, Geraldo, additional, Louis, Judette, additional, Lydic, Ralph, additional, Macrea, Madalina, additional, Maddox, Mary Halsey, additional, Mahowald, Mark W., additional, Malhotra, Atul, additional, Malkani, Roneil G., additional, Malow, Beth A., additional, Manber, Rachel, additional, Manfredini, Daniele, additional, Maquet, Pierre, additional, Marin, Jose M., additional, Masor, Jeffrey, additional, McCrae, Christina S., additional, McGinty, Dennis, additional, Mehra, Reena, additional, Mellman, Thomas A., additional, Mendelson, Wallace B., additional, Mignot, Emmanuel, additional, Minkel, Jared D., additional, A. Mittleman, Murray, additional, Mohsenin, Vahid, additional, Mokhlesi, Babak, additional, Montplaisir, Jacques, additional, Morin, Charles M., additional, Morrell, Mary J., additional, Moul, Douglas E., additional, Nielsen, Tore, additional, Nieto, F. Javier, additional, Nishino, Seiji, additional, Nofzinger, Eric A., additional, O'Brien, Louise M., additional, O'Hara, Bruce F., additional, Olson, Eric J., additional, Ong, Jason C., additional, Opp, Mark R., additional, Pace-Schott, Edward F., additional, Pack, Allan I., additional, Paesani, Daniel A., additional, Park, John G., additional, Parrino, Liborio, additional, Patil, Susheel P., additional, Pavlova, Milena K., additional, Peever, John H., additional, Peigneux, Philippe, additional, Peker, Yüksel, additional, Pelayo, Rafael, additional, Penzel, Thomas, additional, Pépin, Jean-Louis, additional, Peppard, Paul E., additional, Perlis, Michael Lloyd, additional, Perogamvros, Lampros, additional, Perski, Aleksander, additional, Petit, Dominique, additional, Petrov, Megan E., additional, Philip, Pierre, additional, Phillips, Barbara A., additional, Picchioni, Dante, additional, Pigeon, Wilfred R., additional, Pisani, Margaret A., additional, Pliska, Benjamin T., additional, Postuma, Ronald, additional, Quo, Stacey Dagmar, additional, Ramar, Kannan, additional, Randazzo, Angela C., additional, Raphael, Karen G., additional, Redline, Susan, additional, Reid, Kathryn J., additional, Rielly, Albert, additional, Wilhelm Riemann, Dieter, additional, Roehrs, Timothy, additional, Rosenwasser, Alan M., additional, Rosenzweig, Ivana, additional, Roth, Thomas, additional, Rowley, James A., additional, Sagaspe, Patricia, additional, Salas, Rachel E., additional, Sallinen, Mikael, additional, Samuels, Charles, additional, Sanders, Anne E., additional, Saper, Clifford B., additional, Sateia, Michael J., additional, Savard, Josée, additional, Savard, Marie-Hélène, additional, Scharf, Steven M., additional, Schredl, Michael, additional, Schwartz, Sophie, additional, Schweitzer, Paula K., additional, Scullin, Michael K., additional, Sériès, Frédéric, additional, Sessle, Barry J., additional, Sharafkhaneh, Amir, additional, Sharkey, Katherine M., additional, Shiromani, Priyattam J., additional, Shochat, Tamar, additional, Siegel, Jerome M., additional, Silber, Michael H., additional, Simmons, Michael, additional, Smith, Carlyle, additional, Smith, Michael T., additional, Soehner, Adriane M., additional, Somers, Virend K., additional, Spoormaker, Victor I., additional, St. Louis, Erik K., additional, Stein, Murray B., additional, Stickgold, Robert, additional, Stone, Katie L., additional, Stoohs, Riccardo, additional, Stremler, Robyn, additional, Strohl, Kingman P., additional, Svensson, Peter, additional, Szabo, Steven T., additional, Szymusiak, Ronald, additional, Tafti, Mehdi, additional, Taillard, Jacques, additional, Tasali, Esra, additional, Taylor, Daniel J., additional, Teodorescu, Mihai C., additional, Terzano, Mario Giovanni, additional, Thomas, Robert Joseph, additional, Thorpy, Michael J., additional, Tranah, Gregory J., additional, Trenkwalder, Claudia, additional, Turek, Fred W., additional, Tyagi, Shachi, additional, Upender, Raghu Pishka, additional, Valko, Philipp O., additional, Cauter, Eve Van, additional, van de Loo, Aurora J.A.E., additional, van den Berg, Margo, additional, Vanderveken, Olivier M., additional, Van Dongen, Hans P.A., additional, Vaughn, Bradley V., additional, Verrier, Richard L., additional, Verster, Joris C., additional, Vgontzas, Alexandros N., additional, Vila, Bryan, additional, Vitaterna, Martha Hotz, additional, Walsh, James K., additional, Walters, Arthur Scott, additional, Wamsley, Erin J., additional, Watson, Paula L., additional, Weaver, Edward M., additional, Weaver, Terri E., additional, Wesensten, Nancy J., additional, Winocur, Ephraim, additional, Wolfson, Amy R., additional, Won, Christine, additional, Wright, Kenneth P., additional, Wu, Lora J., additional, Wu, Mark, additional, Young, Terry, additional, Zadra, Antonio, additional, Zee, Phyllis C., additional, Zhang, Chunbai, additional, Zinchuk, Andrey V., additional, and Zou, Ding, additional

Published
2017
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29. The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

Author

Holm, Anja, Possovre, Marie Laure, Bandarabadi, Mojtaba, Moseholm, Kristine F., Justinussen, Jessica L., Bozic, Ivan, Lemcke, René, Arribat, Yoan, Amati, Francesca, Silahtaroglu, Asli, Juventin, Maxime, Adamantidis, Antoine, Tafti, Mehdi, Kornum, Birgitte R., Holm, Anja, Possovre, Marie Laure, Bandarabadi, Mojtaba, Moseholm, Kristine F., Justinussen, Jessica L., Bozic, Ivan, Lemcke, René, Arribat, Yoan, Amati, Francesca, Silahtaroglu, Asli, Juventin, Maxime, Adamantidis, Antoine, Tafti, Mehdi, and Kornum, Birgitte R.

Abstract

SignificanceThe hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt. We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep-wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep-wake regulatory role of miR-137.

Published
2022

31. Dreaming without REM sleep

Author

Oudiette, Delphine, Dealberto, Marie-José, Uguccioni, Ginevra, Golmard, Jean-Louis, Merino-Andreu, Milagros, Tafti, Mehdi, Garma, Lucile, Schwartz, Sophie, and Arnulf, Isabelle

Published
2012
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33. The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

Author

Holm, Anja, primary, Possovre, Marie-Laure, additional, Bandarabadi, Mojtaba, additional, Moseholm, Kristine F., additional, Justinussen, Jessica L., additional, Bozic, Ivan, additional, Lemcke, René, additional, Arribat, Yoan, additional, Amati, Francesca, additional, Silahtaroglu, Asli, additional, Juventin, Maxime, additional, Adamantidis, Antoine, additional, Tafti, Mehdi, additional, and Kornum, Birgitte R., additional

Published
2022
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38. The European Narcolepsy Network (EU-NN) database

Author

Khatami, Ramin, Luca, Gianina, Baumann, Christian R., Bassetti, Claudio L., Bruni, Oliviero, Canellas, Francesca, Dauvilliers, Yves, Del Rio-Villegas, Rafael, Feketeova, Eva, Ferri, Raffaele, Geisler, Peter, Högl, Birgit, Jennum, Poul, Kornum, Birgitte R., Lecendreux, Michel, Martins-da-Silva, Antonio, Mathis, Johannes, Mayer, Geert, Paiva, Teresa, Partinen, Markku, Peraita-Adrados, Rosa, Plazzi, Guiseppe, Santamaria, Joan, Sonka, Karel, Riha, Renata, Tafti, Mehdi, Wierzbicka, Aleksandra, Young, Peter, Lammers, Gert Jan, and Overeem, Sebastiaan

Published
2016
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42. Narcolepsy with cataplexy is caused by epigenetic silencing of hypocretin neurons

Author

Seifinejad, Ali, primary, Neiteler, Almar, additional, Li, Sha, additional, Pfister, Corinne, additional, Fronczek, Rolf, additional, Shan, Ling, additional, Garrett-Sinha, Lee A., additional, Frieser, David, additional, Honda, Makoto, additional, Arribat, Yoan, additional, Grepper, Dogan, additional, Amati, Francesca, additional, Picot, Marie, additional, Iseli, Christian, additional, Chartrel, Nicolas, additional, Lammers, Gert J., additional, Liblau, Roland, additional, Vassalli, Anne, additional, and Tafti, Mehdi, additional

Published
2021
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44. Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

Author

Tafti, Mehdi, Lammers, Gert J., Dauvilliers, Yves, Overeem, Sebastiaan, Mayer, Geert, Nowak, Jacek, Pfister, Corinne, Dubois, Valérie, Eliaou, Jean-François, Eberhard, Hans-Peter, Liblau, Roland, Wierzbicka, Aleksandra, Geisler, Peter, Bassetti, Claudio L., Mathis, Johannes, Lecendreux, Michel, Khatami, Ramin, Heinzer, Raphaël, Haba-Rubio, José, Feketeova, Eva, Baumann, Christian R., Kutalik, Zoltán, Tiercy, Jean-Marie, Tafti, Mehdi, Lammers, Gert J., Dauvilliers, Yves, Overeem, Sebastiaan, Mayer, Geert, Nowak, Jacek, Pfister, Corinne, Dubois, Valérie, Eliaou, Jean-François, Eberhard, Hans-Peter, Liblau, Roland, Wierzbicka, Aleksandra, Geisler, Peter, Bassetti, Claudio L., Mathis, Johannes, Lecendreux, Michel, Khatami, Ramin, Heinzer, Raphaël, Haba-Rubio, José, Feketeova, Eva, Baumann, Christian R., Kutalik, Zoltán, and Tiercy, Jean-Marie

Abstract

Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15-1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Significance Although evidence strongly indicates that immune-related mechanisms are involved in the pathogenesis of narcolepsy with hypocretin deficiency, functional data are missing. The strong association with HLA class II genes is not corroborated by any CD4+ T Cell implication and inflammation. Additionally, these genes are not normally expressed in the brain. Here, we show that several HLA class I variants are associated with narcolepsy. Since these mol

Published
2021

46. Sleep Characteristics in Early Stages of Chronic Kidney Disease in the HypnoLaus Cohort

Author

Ogna, Adam, Ogna, Valentina Forni, Rubio, José Haba, Tobback, Nadia, Andries, Dana, Preisig, Martin, Tafti, Mehdi, Vollenweider, Peter, Waeber, Gerard, Marques-Vidal, Pedro, Heinzer, Raphaël, Ogna, Adam, Ogna, Valentina Forni, Rubio, José Haba, Tobback, Nadia, Andries, Dana, Preisig, Martin, Tafti, Mehdi, Vollenweider, Peter, Waeber, Gerard, Marques-Vidal, Pedro, and Heinzer, Raphaël

Abstract

Study Objectives To evaluate the association between early stages of chronic kidney disease (CKD) and sleep disordered breathing (SDB), restless legs syndrome (RLS), and subjective and objective sleep quality (SQ). Methods Cross-sectional analysis of a general population-based cohort (HypnoLaus). 1,760 adults (862 men, 898 women; age 59.3 (± 11.4) y) underwent complete polysomnography at home. Results 8.2% of participants had mild CKD (stage 1-2, estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2 with albuminuria) and 7.8% moderate CKD (stage 3, eGFR 30-60 mL/min/1.73 m2). 37.3% of our sample had moderate-to-severe SDB (apnea-hypopnea index [AHI] ≥ 15/h) and 15.3% had severe SDB (AHI ≥ 30/h). SDB prevalence was positively associated with CKD stages and negatively with eGFR. In multivariate analysis, age, male sex, and body mass index were independently associated with SDB (all P < 0.001), but kidney function was not. The prevalence of RLS was 17.5%, without difference between CKD stages. Periodic leg movements index (PLMI) was independently associated with CKD stages. Subjective and objective SQ decreased and the use of sleep medication was more frequent with declining kidney function. Older age, female sex, and the severity of SDB were the strongest predictors of poor SQ in multivariate regression analysis but CKD stage was also independently associated with reduced objective SQ. Conclusions Patients with early stages of CKD have impaired SQ, use more hypnotic drugs, and have an increased prevalence of SDB and PLM. After controlling for confounders, objective SQ and PLMI were still independently associated with declining kidney function. Significance Analyzing a large population-based cohort by polysomnography, we observed an independent association between declining kidney function, objective sleep quality and periodic leg movements. Conversely, the increased prevalence of sleep disordered breathing in early stages of chronic kidney disease s

Published
2021

47. The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study

Author

Dietmann, Anelia; https://orcid.org/0000-0002-8949-0645, Wenz, Elena; https://orcid.org/0000-0002-6231-3358, van der Meer, Julia; https://orcid.org/0000-0002-1913-5146, Ringli, Maya, Warncke, Jan D; https://orcid.org/0000-0001-6852-4191, Edwards, Ellen; https://orcid.org/0000-0003-1986-1831, Schmidt, Markus H; https://orcid.org/0000-0002-3299-1318, Bernasconi, Corrado A; https://orcid.org/0000-0002-1019-5468, Nirkko, Arto, Strub, Mathias, Miano, Silvia; https://orcid.org/0000-0003-4475-3947, Manconi, Mauro; https://orcid.org/0000-0002-1849-7196, Acker, Jens; https://orcid.org/0000-0002-5875-656X, von Manitius, Sigrid, Baumann, Christian R; https://orcid.org/0000-0003-3417-1978, Valko, Philip O; https://orcid.org/0000-0002-8435-1697, Yilmaz, Bahtiyar; https://orcid.org/0000-0003-1888-9226, Brunner, Andreas-David; https://orcid.org/0000-0002-2733-7899, Tzovara, Athina; https://orcid.org/0000-0002-7588-1418, Zhang, Zhongxing; https://orcid.org/0000-0003-0184-8882, Largiadèr, Carlo R; https://orcid.org/0000-0002-0889-8922, Tafti, Mehdi; https://orcid.org/0000-0002-6997-3914, Latorre, Daniela; https://orcid.org/0000-0003-1031-1534, Sallusto, Federica; https://orcid.org/0000-0003-3750-2752, Khatami, Ramin, Bassetti, Claudio L A; https://orcid.org/0000-0002-4535-0245, Dietmann, Anelia; https://orcid.org/0000-0002-8949-0645, Wenz, Elena; https://orcid.org/0000-0002-6231-3358, van der Meer, Julia; https://orcid.org/0000-0002-1913-5146, Ringli, Maya, Warncke, Jan D; https://orcid.org/0000-0001-6852-4191, Edwards, Ellen; https://orcid.org/0000-0003-1986-1831, Schmidt, Markus H; https://orcid.org/0000-0002-3299-1318, Bernasconi, Corrado A; https://orcid.org/0000-0002-1019-5468, Nirkko, Arto, Strub, Mathias, Miano, Silvia; https://orcid.org/0000-0003-4475-3947, Manconi, Mauro; https://orcid.org/0000-0002-1849-7196, Acker, Jens; https://orcid.org/0000-0002-5875-656X, von Manitius, Sigrid, Baumann, Christian R; https://orcid.org/0000-0003-3417-1978, Valko, Philip O; https://orcid.org/0000-0002-8435-1697, Yilmaz, Bahtiyar; https://orcid.org/0000-0003-1888-9226, Brunner, Andreas-David; https://orcid.org/0000-0002-2733-7899, Tzovara, Athina; https://orcid.org/0000-0002-7588-1418, Zhang, Zhongxing; https://orcid.org/0000-0003-0184-8882, Largiadèr, Carlo R; https://orcid.org/0000-0002-0889-8922, Tafti, Mehdi; https://orcid.org/0000-0002-6997-3914, Latorre, Daniela; https://orcid.org/0000-0003-1031-1534, Sallusto, Federica; https://orcid.org/0000-0003-3750-2752, Khatami, Ramin, and Bassetti, Claudio L A; https://orcid.org/0000-0002-4535-0245

Abstract

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagn

Published
2021

50. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients

Author

Cvetkovic-Lopes, Vesna, Bayer, Laurence, Dorsaz, Stephane, Maret, Stephanie, Pradervand, Sylvain, Dauvilliers, Yves, Lecendreux, Michel, Lammers, Gert-Jan, Donjacour, Claire E.H.M., Pasquier, Renaud A. Du, Pfister, Corinne, Petit, Brice, Hor, Hyun, Muhlethaler, Michel, and Tafti, Mehdi

Subjects
Gene expression -- Research -- Usage -- Genetic aspects, Enzyme-linked immunosorbent assay -- Usage -- Research, Narcolepsy -- Genetic aspects -- Care and treatment -- Research, Apoptosis -- Research -- Usage -- Genetic aspects, Health care industry
Abstract

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder., Introduction Hypocretin (orexin) neurons play a critical role in the regulation of sleep and wakefulness, and disturbances of the hypocretin system have been directly linked to narcolepsy in animals and [...]

Published
2010
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