http://hdl.handle.net/10993/106 Search this channel search https://orbilu.uni.lu/simple-search http://hdl.handle.net/10993/56062 Title: HLA in isolated REM sleep behavior disorder and Lewy body dementia <br/> <br/>Author, co-author: Yu, Eric; Krohn, Lynne; Ruskey, Jennifer A.; Asayesh, Farnaz; Spiegelman, Dan; Shah, Zalak; Chia, Ruth; Arnulf, Isabelle; Hu, Michele T. M.; Montplaisir, Jacques Y.; Gagnon, Jean-François; Desautels, Alex; Dauvilliers, Yves; Gigli, Gian Luigi; Valente, Mariarosaria; Janes, Francesco; Bernardini, Andrea; Högl, Birgit; Stefani, Ambra; Ibrahim, Abubaker; Heidbreder, Anna; Sonka, Karel; Dusek, Petr; Kemlink, David; Oertel, Wolfgang; Janzen, Annette; Plazzi, Giuseppe; Antelmi, Elena; Figorilli, Michela; Puligheddu, Monica; Mollenhauer, Brit; Trenkwalder, Claudia; Sixel-Döring, Friederike; Cochen De Cock, Valérie; Ferini-Strambi, Luigi; Dijkstra, Femke; Viaene, Mineke; Abril, Beatriz; Boeve, Bradley F.; Rouleau, Guy A.; Postuma, Ronald B.; May, Patrick; Krüger, Rejko; Consortium, The International L. B. D. Genomics; Scholz, Sonja W.; Gan-Or, Ziv <br/> <br/>Abstract: Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95 CI = 1.27–1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95\%CI = 1.12–1.41, p = 8.76e-05), 70Q (OR = 0.81, 95\%CI = 0.72–0.91, p = 3.65e-04) and 71R (OR = 1.21, 95\%CI = 1.08–1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies. Mon, 16 Oct 2023 03:31:03 GMT http://hdl.handle.net/10993/56056 Title: mTOR-dependent translation amplifies microglia priming in aging mice. <br/> <br/>Author, co-author: Keane, Lily; Antignano, Ignazio; Riechers, Sean-Patrick Hermann; Zollinger, Raphael; Dumas, Anaelle A.; Offermann, Nina; Bernis, Maria E.; Russ, Jenny; Graelmann, Frederike; McCormick, Patrick Neil; Esser, Julia; Tejera, Dario; Nagano, Ai; Wang, Jun; Chelala, Claude; Biederbick, Yvonne; Halle, Annett; Salomoni, Paolo; Heneka, Michael; Capasso, Melania <br/> <br/>Abstract: Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice had upregulated mTOR complex 1 signaling controlling translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual yet contrasting effect on microglia priming: it caused an NF-κB-dependent upregulation of priming genes at the mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation, and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration. Fri, 13 Oct 2023 03:30:36 GMT http://hdl.handle.net/10993/56044 Title: GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture <br/> <br/>Author, co-author: Stevelink, Remi; Campbell, Ciarán; Chen, Siwei; Abou-Khalil, Bassel; Adesoji, Oluyomi M.; Afawi, Zaid; Amadori, Elisabetta; Anderson, Alison; Anderson, Joseph; Andrade, Danielle M.; Annesi, Grazia; Auce, Pauls; Avbersek, Andreja; Bahlo, Melanie; Baker, Mark D.; Balagura, Ganna; Balestrini, Simona; Barba, Carmen; Barboza, Karen; Bartolomei, Fabrice; Bast, Thomas; Baum, Larry; Baumgartner, Tobias; Baykan, Betül; Bebek, Nerses; Becker, Albert J.; Becker, Felicitas; Bennett, Caitlin A.; Berghuis, Bianca; Berkovic, Samuel F.; Beydoun, Ahmad; Bianchini, Claudia; Bisulli, Francesca; Blatt, Ilan; Bobbili, Dheeraj Reddy; Borggraefe, Ingo; Bosselmann, Christian; Braatz, Vera; Bradfield, Jonathan P.; Brockmann, Knut; Brody, Lawrence C.; Buono, Russell J.; Busch, Robyn M.; Caglayan, Hande; Campbell, Ellen; Canafoglia, Laura; Canavati, Christina; Cascino, Gregory D.; Castellotti, Barbara; Catarino, Claudia B.; Cavalleri, Gianpiero L.; Cerrato, Felecia; Chassoux, Francine; Cherny, Stacey S.; Cheung, Ching-Lung; Chinthapalli, Krishna; Chou, I.-Jun; Chung, Seo-Kyung; Churchhouse, Claire; Clark, Peggy O.; Cole, Andrew J.; Compston, Alastair; Coppola, Antonietta; Cosico, Mahgenn; Cossette, Patrick; Craig, John J.; Cusick, Caroline; Daly, Mark J.; Davis, Lea K.; de Haan, Gerrit-Jan; Delanty, Norman; Depondt, Chantal; Derambure, Philippe; Devinsky, Orrin; Di Vito, Lidia; Dlugos, Dennis J.; Doccini, Viola; Doherty, Colin P.; El-Naggar, Hany; Elger, Christian E.; Ellis, Colin A.; Eriksson, Johan G.; Faucon, Annika; Feng, Yen-Chen A.; Ferguson, Lisa; Ferraro, Thomas N.; Ferri, Lorenzo; Feucht, Martha; Fitzgerald, Mark; Fonferko-Shadrach, Beata; Fortunato, Francesco; Franceschetti, Silvana; Franke, Andre; French, Jacqueline A.; Freri, Elena; Gagliardi, Monica; Gambardella, Antonio; Geller, Eric B.; Giangregorio, Tania; Gjerstad, Leif; Glauser, Tracy; Goldberg, Ethan; Goldman, Alicia; Granata, Tiziana; Greenberg, David A.; Guerrini, Renzo; Gupta, Namrata; Haas, Kevin F.; Hakonarson, Hakon; Hallmann, Kerstin; Hassanin, Emadeldin Saeed Fathy Sayed; Hegde, Manu; Heinzen, Erin L.; Helbig, Ingo; Hengsbach, Christian; Heyne, Henrike O.; Hirose, Shinichi; Hirsch, Edouard; Hjalgrim, Helle; Howrigan, Daniel P.; Hucks, Donald; Hung, Po-Cheng; Iacomino, Michele; Imbach, Lukas L.; Inoue, Yushi; Ishii, Atsushi; Jamnadas-Khoda, Jennifer; Jehi, Lara; Johnson, Michael R.; Kälviäinen, Reetta; Kamatani, Yoichiro; Kanaan, Moien; Kanai, Masahiro; Kantanen, Anne-Mari; Kara, Bülent; Kariuki, Symon M.; Kasperavičiūte, Dalia; Kasteleijn-Nolst Trenite, Dorothee; Kato, Mitsuhiro; Kegele, Josua; Kesim, Yeşim; Khoueiry-Zgheib, Nathalie; King, Chontelle; Kirsch, Heidi E.; Klein, Karl M.; Kluger, Gerhard; Knake, Susanne; Knowlton, Robert C.; Koeleman, Bobby P. C.; Korczyn, Amos D.; Koupparis, Andreas; Kousiappa, Ioanna; Krause, Roland; Krenn, Martin; Krestel, Heinz; Krey, Ilona; Kunz, Wolfram S.; Kurki, Mitja I.; Kurlemann, Gerhard; Kuzniecky, Ruben; Kwan, Patrick; Labate, Angelo; Lacey, Austin; Lal, Dennis; Landoulsi, Zied; Lau, Yu-Lung; Lauxmann, Stephen; Leech, Stephanie L.; Lehesjoki, Anna-Elina; Lemke, Johannes R.; Lerche, Holger; Lesca, Gaetan; Leu, Costin; Lewin, Naomi; Lewis-Smith, David; Li, Gloria H.-Y.; Li, Qingqin S.; Licchetta, Laura; Lin, Kuang-Lin; Lindhout, Dick; Linnankivi, Tarja; Lopes-Cendes, Iscia; Lowenstein, Daniel H.; Lui, Colin H. T.; Madia, Francesca; Magnusson, Sigurdur; Marson, Anthony G.; May, Patrick; McGraw, Christopher M.; Mei, Davide; Mills, James L.; Minardi, Raffaella; Mirza, Nasir; Møller, Rikke S.; Molloy, Anne M.; Montomoli, Martino; Mostacci, Barbara; Muccioli, Lorenzo; Muhle, Hiltrud; Müller-Schlüter, Karen; Najm, Imad M.; Nasreddine, Wassim; Neale, Benjamin M.; Neubauer, Bernd; Newton, Charles R. J. C.; Nöthen, Markus M.; Nothnagel, Michael; Nürnberg, Peter; O’Brien, Terence J.; Okada, Yukinori; Ólafsson, Elías; Oliver, Karen L.; Özkara, Çiğdem; Palotie, Aarno; Pangilinan, Faith; Papacostas, Savvas S.; Parrini, Elena; Pato, Carlos N.; Pato, Michele T.; Pendziwiat, Manuela; Petrovski, Slavé; Pickrell, William O.; Pinsky, Rebecca; Pippucci, Tommaso; Poduri, Annapurna; Pondrelli, Federica; Powell, Rob H. W.; Privitera, Michael; Rademacher, Annika; Radtke, Rodney; Ragona, Francesca; Rau, Sarah; Rees, Mark I.; Regan, Brigid M.; Reif, Philipp S.; Rhelms, Sylvain; Riva, Antonella; Rosenow, Felix; Ryvlin, Philippe; Saarela, Anni; Sadleir, Lynette G.; Sander, Josemir W.; Sander, Thomas; Scala, Marcello; Scattergood, Theresa; Schachter, Steven C.; Schankin, Christoph J.; Scheffer, Ingrid E.; Schmitz, Bettina; Schoch, Susanne; Schubert-Bast, Susanne; Schulze-Bonhage, Andreas; Scudieri, Paolo; Sham, Pak; Sheidley, Beth R.; Shih, Jerry J.; Sills, Graeme J.; Sisodiya, Sanjay M.; Smith, Michael C.; Smith, Philip E.; Sonsma, Anja C. M.; Speed, Doug; Sperling, Michael R.; Stefansson, Hreinn; Stefansson, Kári; Steinhoff, Bernhard J.; Stephani, Ulrich; Stewart, William C.; Stipa, Carlotta; Striano, Pasquale; Stroink, Hans; Strzelczyk, Adam; Surges, Rainer; Suzuki, Toshimitsu; Tan, K. Meng; Taneja, R. S.; Tanteles, George A.; Taubøll, Erik; Thio, Liu Lin; Thomas, G. Neil; Thomas, Rhys H.; Timonen, Oskari; Tinuper, Paolo; Todaro, Marian; Topaloğlu, Pınar; Tozzi, Rossana; Tsai, Meng-Han; Tumiene, Birute; Turkdogan, Dilsad; Unnsteinsdóttir, Unnur; Utkus, Algirdas; Vaidiswaran, Priya; Valton, Luc; van Baalen, Andreas; Vetro, Annalisa; Vining, Eileen P. G.; Visscher, Frank; von Brauchitsch, Sophie; von Wrede, Randi; Epilepsies, International League Against Epilepsy Consortium On Complex <br/> <br/>Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6 and 90 of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment. Sun, 01 Oct 2023 03:30:44 GMT http://hdl.handle.net/10993/55954 Title: Neurons undergo pathogenic metabolic reprogramming in models of familial ALS. <br/> <br/>Author, co-author: Riechers, Sean-Patrick Hermann; Mojsilovic-Petrovic, Jelena; Belton, Tayler B.; Chakrabarty, Ram P.; Garjani, Mehraveh; Medvedeva, Valentina; Dalton, Casey; Wong, Yvette C.; Chandel, Navdeep S.; Dienel, Gerald; Kalb, Robert G. <br/> <br/>Abstract: OBJECTIVES: Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis [ALS]), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We investigated intermediary metabolism of neurons expressing familial ALS (fALS) genes and interrogated the functional consequences of glycolysis genes in fitness assays and neuronal survival. METHODS: We created a pure neuronal model system for isotopologue investigations of fuel utilization. In a yeast platform we studied the functional contributions of glycolysis genes in a growth fitness assay iafter expressing of a fALS gene. RESULTS: We find in our rodent models of fALS, a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics, and redox status, thus supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. CONCLUSIONS: We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful. <br/> <br/>Commentary: Published by Elsevier GmbH. Tue, 12 Sep 2023 14:08:26 GMT http://hdl.handle.net/10993/55953 Title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. <br/> <br/>Author, co-author: Haenig, Christian; Atias, Nir; Taylor, Alexander K.; Mazza, Arnon; Schaefer, Martin H.; Russ, Jenny; Riechers, Sean-Patrick Hermann; Jain, Shushant; Coughlin, Maura; Fontaine, Jean-Fred; Freibaum, Brian D.; Brusendorf, Lydia; Zenkner, Martina; Porras, Pablo; Stroedicke, Martin; Schnoegl, Sigrid; Arnsburg, Kristin; Boeddrich, Annett; Pigazzini, Lucia; Heutink, Peter; Taylor, J. Paul; Kirstein, Janine; Andrade-Navarro, Miguel A.; Sharan, Roded; Wanker, Erich E. <br/> <br/>Abstract: Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs. It facilitates the identification of interacting proteins that significantly influence mutant TDP-43 and HTT toxicity in transgenic flies, as well as of ARF-GEP(100) that controls misfolding and aggregation of multiple ND-causing proteins in experimental model systems. Furthermore, it enables the prediction of ND-specific subnetworks and the identification of proteins, such as ATXN1 and MKL1, that are abnormally aggregated in postmortem brains of Alzheimer's disease patients, suggesting widespread protein aggregation in NDs. <br/> <br/>Commentary: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. Tue, 12 Sep 2023 13:50:34 GMT http://hdl.handle.net/10993/55952 Title: Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process. <br/> <br/>Author, co-author: Lessard-Beaudoin, Mélissa; Laroche, Mélissa; Loudghi, Amal; Demers, Marie-Josée; Denault, Jean-Bernard; Grenier, Guillaume; Riechers, Sean-Patrick Hermann; Wanker, Erich E.; Graham, Rona K. <br/> <br/>Abstract: Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the serine/threonine kinase family is involved in apoptosis and serine/threonine kinase 3 (STK3) is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7, and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7, and -8 expression and activity vary significantly among the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or nonapoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration. <br/> <br/>Commentary: Copyright © 2016 Elsevier Inc. All rights reserved. Tue, 12 Sep 2023 13:46:36 GMT http://hdl.handle.net/10993/55951 Title: Age-dependent differential expression of death-associated protein 6 (Daxx) in various peripheral tissues and different brain regions of C57BL/6 male mice. <br/> <br/>Author, co-author: Lessard-Beaudoin, Mélissa; Laroche, Mélissa; Demers, Marie-Josée; Duclos, Catherine; Denault, Jean-Bernard; Grenier, Guillaume; Riechers, Sean-Patrick Hermann; Wanker, Erich E.; Graham, Rona K. <br/> <br/>Abstract: Death-associated protein 6 (DAXX) is a ubiquitous protein implicated in various cellular processes such as apoptosis, tumorigenesis, development and transcription. The role of DAXX is however ambiguous and many contradictory results regarding its function in apoptosis upon various cellular stresses are described in the literature. In order to have a better understanding of the role of DAXX throughout the entire organism under physiological stress conditions, we have characterized the mRNA levels, protein expression and the proteolytic processing of DAXX in the normal aging process in peripheral organs and brain regions in C57BL/6 male mice. Overall, Daxx mRNA expression decreases with aging in the liver, kidney, heart, cortex and cerebellum. In contrast, an increase is observed in the striatum. The protein expression of DAXX and of its proteolytic fragments increases with aging in the kidney, heart and cortex. In liver and spleen, no changes are observed while in the striatum and cerebellum, certain forms increase and others decrease with age, suggesting that the functions of DAXX may be cell type dependent. This study provides important details regarding the expression and post-translational modifications of DAXX in aging in the entire organism and provides reference data for the deregulation observed in age-associated diseases. Tue, 12 Sep 2023 13:42:12 GMT http://hdl.handle.net/10993/55950 Title: Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD. <br/> <br/>Author, co-author: Riechers, Sean-Patrick Hermann; Butland, Stefanie; Deng, Yu; Skotte, Niels; Ehrnhoefer, Dagmar E.; Russ, Jenny; Laine, Jean; Laroche, Melissa; Pouladi, Mahmoud A.; Wanker, Erich E.; Hayden, Michael R.; Graham, Rona K. <br/> <br/>Abstract: Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein-protein interactions, we performed a high-throughput yeast-2-hybrid (Y2H) screen against ∼17,000 human proteins to gain further insight into the function of CASP6. We identified a high-confidence list of 87 potential CASP6 interactors. From this list, 61% are predicted to contain a CASP6 recognition site. Of nine candidate substrates assessed, six are cleaved by CASP6. Proteins that did not contain a predicted CASP6 recognition site were assessed using a LUMIER assay approach, and 51% were further validated as interactors by this method. Of note, 54% of the high-confidence interactors identified show alterations in human HD brain at the mRNA level, and there is a significant enrichment for previously validated huntingtin (HTT) interactors. One protein of interest, STK3, a pro-apoptotic kinase, was validated biochemically to be a CASP6 substrate. Furthermore, our results demonstrate that in striatal cells expressing mutant huntingtin (mHTT), an increase in full length and fragment levels of STK3 are observed. We further show that caspase-3 is not essential for the endogenous cleavage of STK3. Characterization of the interaction network provides important new information regarding key pathways of interactors of CASP6 and highlights potential novel therapeutic targets for HD, AD and cerebral ischemia. <br/> <br/>Commentary: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. Tue, 12 Sep 2023 13:35:44 GMT http://hdl.handle.net/10993/55949 Title: Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. <br/> <br/>Author, co-author: Stroedicke, Martin; Bounab, Yacine; Strempel, Nadine; Klockmeier, Konrad; Yigit, Sargon; Friedrich, Ralf P.; Chaurasia, Gautam; Li, Shuang; Hesse, Franziska; Riechers, Sean-Patrick Hermann; Russ, Jenny; Nicoletti, Cecilia; Boeddrich, Annett; Wiglenda, Thomas; Haenig, Christian; Schnoegl, Sigrid; Fournier, David; Graham, Rona K.; Hayden, Michael R.; Sigrist, Stephan; Bates, Gillian P.; Priller, Josef; Andrade-Navarro, Miguel A.; Futschik, Matthias E.; Wanker, Erich E. <br/> <br/>Abstract: Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins. <br/> <br/>Commentary: © 2015 Stroedicke et al.; Published by Cold Spring Harbor Laboratory Press. Tue, 12 Sep 2023 13:32:33 GMT http://hdl.handle.net/10993/55948 Title: The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease. <br/> <br/>Author, co-author: Butland, Stefanie L.; Sanders, Shaun S.; Schmidt, Mandi E.; Riechers, Sean-Patrick Hermann; Lin, David T. S.; Martin, Dale D. O.; Vaid, Kuljeet; Graham, Rona K.; Singaraja, Roshni R.; Wanker, Erich E.; Conibear, Elizabeth; Hayden, Michael R. <br/> <br/>Abstract: HIP14 is the most highly conserved of 23 human palmitoyl acyltransferases (PATs) that catalyze the post-translational addition of palmitate to proteins, including huntingtin (HTT). HIP14 is dysfunctional in the presence of mutant HTT (mHTT), the causative gene for Huntington disease (HD), and we hypothesize that reduced palmitoylation of HTT and other HIP14 substrates contributes to the pathogenesis of the disease. Here we describe the yeast two-hybrid (Y2H) interactors of HIP14 in the first comprehensive study of interactors of a mammalian PAT. Unexpectedly, we discovered a highly significant overlap between HIP14 interactors and 370 published interactors of HTT, 4-fold greater than for control proteins (P = 8 × 10(-5)). Nearly half of the 36 shared interactors are already implicated in HD, supporting a direct link between HIP14 and the disease. The HIP14 Y2H interaction set is significantly enriched for palmitoylated proteins that are candidate substrates. We confirmed that three of them, GPM6A, and the Sprouty domain-containing proteins SPRED1 and SPRED3, are indeed palmitoylated by HIP14; the first enzyme known to palmitoylate these proteins. These novel substrates functions might be affected by reduced palmitoylation in HD. We also show that the vesicular cargo adapter optineurin, an established HTT-binding protein, co-immunoprecipitates with HIP14 but is not palmitoylated. mHTT leads to mislocalization of optineurin and aberrant cargo trafficking. Therefore, it is possible that optineurin regulates trafficking of HIP14 to its substrates. Taken together, our data raise the possibility that defective palmitoylation by HIP14 might be an important mechanism that contributes to the pathogenesis of HD. <br/> <br/>Commentary: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. Tue, 12 Sep 2023 13:27:55 GMT http://hdl.handle.net/10993/55947 Title: Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1. <br/> <br/>Author, co-author: Petrakis, Spyros; Raskó, Tamás; Russ, Jenny; Friedrich, Ralf P.; Stroedicke, Martin; Riechers, Sean-Patrick Hermann; Muehlenberg, Katja; Möller, Angeli; Reinhardt, Anita; Vinayagam, Arunachalam; Schaefer, Martin H.; Boutros, Michael; Tricoire, Hervé; Andrade-Navarro, Miguel A.; Wanker, Erich E. <br/> <br/>Abstract: Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1-interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo. Tue, 12 Sep 2023 13:23:22 GMT http://hdl.handle.net/10993/55860 Title: SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis <br/> <br/>Author, co-author: Stefanski, Arthur; Pérez-Palma, Eduardo; Brünger, Tobias; Montanucci, Ludovica; Gati, Cornelius; Klöckner, Chiara; Johannesen, Katrine M.; Goodspeed, Kimberly; Macnee, Marie; Deng, Alexander T.; Aledo-Serrano, Ángel; Borovikov, Artem; Kava, Maina; Bouman, Arjan M.; Hajianpour, M. J.; Pal, Deb K.; Engelen, Marc; Hagebeuk, Eveline E. O.; Shinawi, Marwan; Heidlebaugh, Alexis R.; Oetjens, Kathryn; Hoffman, Trevor L.; Striano, Pasquale; Freed, Amanda S.; Futtrup, Line; Balslev, Thomas; Abulí, Anna; Danvoye, Leslie; Lederer, Damien; Balci, Tugce; Nabavi Nouri, Maryam; Butler, Elizabeth; Drewes, Sarah; van Engelen, Kalene; Howell, Katherine B.; Khoury, Jean; May, Patrick; Trinidad, Marena; Froelich, Steven; Lemke, Johannes R.; Tiller, Jacob; Freed, Amber N.; Kang, Jing-Qiong; Wuster, Arthur; Møller, Rikke S.; Lal, Dennis <br/> <br/>Abstract: Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function, and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6, and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function, and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 Portal (https://slc6a1-portal.broadinstitute.org/). Thu, 31 Aug 2023 19:26:06 GMT http://hdl.handle.net/10993/55826 Title: Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals. <br/> <br/>Author, co-author: Montanucci, Ludovica; Lewis-Smith, David; Collins, Ryan L.; Niestroj, Lisa-Marie; Parthasarathy, Shridhar; Xian, Julie; Ganesan, Shiva; Macnee, Marie; Brünger, Tobias; Thomas, Rhys H.; Talkowski, Michael; Krause, Roland; May, Patrick; Helbig, Ingo; Leu, Costin; Lal, Dennis <br/> <br/>Abstract: Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice. Wed, 23 Aug 2023 03:30:26 GMT http://hdl.handle.net/10993/55617 Title: Validation of a Parkinson's disease questionnaire-39-based functional mobility composite score (FMCS) in people with Parkinson's disease. <br/> <br/>Author, co-author: Hanff, Anne-Marie; McCrum, Christopher; Rauschenberger, Armin; Aguayo, Gloria A.; Zeegers, Maurice P.; Leist, Anja; Krüger, Rejko <br/> <br/>Abstract: INTRODUCTION: Functional mobility is an important outcome for people with Parkinson's disease (PwP). Despite this, there is no established patient-reported outcome measure that serves as a gold standard for assessing patient-reported functional mobility in PwP. We aimed to validate the algorithm calculating the Parkinson's Disease Questionnaire-39 (PDQ-39) based Functional Mobility Composite Score (FMCS). METHODS: We designed a count-based algorithm to measure patient-reported functional mobility in PwP from items of the PDQ-39 subscales mobility and activities of daily living. Convergent validity of the algorithm calculating the PDQ-39-based FMCS was assessed using the objective Timed Up and Go (n = 253) and discriminative validity was assessed by comparing the FMCS with patient-reported (MDS-UPDRS II) and clinician-assessed (MDS-UPDRS III) motor symptoms as well as between disease stages (H&Y) and PIGD phenotypes (n = 736). Participants were between 22 and 92 years old, with a disease duration from 0 to 32 years and 64.9% in a H&Y 1-2 ranging from 1 to 5. RESULTS: Spearman correlation coefficients (r(s)) ranging from -0.45 to -0.77 (p < 0.001) indicated convergent validity. Hence, a t-test suggested sufficient ability of the FMCS to discriminate (p < 0.001) between patient-reported and clinician-assessed motor symptoms. More specifically, FMCS was more strongly associated with patient-reported MDS-UPDRS II (r(s) = -0.77) than clinician-reported MDS-UPDRS III (r(s) = -0.45) and can discriminate between disease stages as between PIGD phenotypes (p < 0.001). CONCLUSION: The FMCS is a valid composite score to assess functional mobility through patient reports in PwP for studying functional mobility in studies using the PDQ-39. <br/> <br/>Commentary: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. Sun, 16 Jul 2023 03:30:32 GMT http://hdl.handle.net/10993/55616 Title: Exploration of whether socioeconomic factors affect the results of priority setting partnerships: updating the top 10 research priorities for the management of Parkinson's in an international setting. <br/> <br/>Author, co-author: Bowring, Francesca; Welch, Jessica; Woodward, Charlotte; Lo, Christine; Lawton, Michael; Sulzer, Patricia; Hanff, Anne-Marie; Krüger, Rejko; Liepelt-Scarfone, Inga; Hu, Michele T. <br/> <br/>Abstract: OBJECTIVES: Explore whether socioeconomic differences of patients affect the prioritisation of pre-existing research questions and explore the agreement between healthcare professionals (HCP) and patients in priority setting partnerships (PSPs). DESIGN AND SETTING: Prospective, three centre survey across UK (400 participants), Tuebingen (176 participants) and Luxembourg (303 participants). People with Parkinson's (PwP), research participants, relatives and HCP associated with three Parkinson's cohort studies were invited to participate, along with linked centres (clinical care settings, research groups, charities). Responders were encouraged to pass on the survey to friends/families/carers. METHODS: The survey involved rating the importance of research questions on a Likert scale, allowing for the generation of one new question participants felt was particularly important. Collection of demographic information allowed for comparisons of priorities across a range of socioeconomic variables; the top 10 research priorities for each group were then compared. Questions added by participants were subject to a thematic analysis. RESULTS: 879 participants completed the survey (58% PwP, 22% family/friends, 13% HCP, 4% carers). Finding the best form of physiotherapy for PwP was the number one priority across the majority of analyses. HCP were the only subgroup not to place physiotherapy in the top 10. Factors most likely to affect prioritisation in PwP included educational level, presence of carer support and disease duration. There was little difference between other socioeconomic categories. CONCLUSIONS: Socioeconomic factors modestly influenced some research priority ratings but did not significantly affect the top priority in most comparisons. Future studies must ensure patients from a range of socioeconomic backgrounds are recruited, ensuring results generalisable to the public while also identifying any key disparities in prioritisation. PSP should also take care that HCP do not skew results during prioritisation of questions, as in this study the most important priority to patients was not identified by professionals. <br/> <br/>Commentary: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. Sun, 16 Jul 2023 03:30:31 GMT http://hdl.handle.net/10993/55468 Title: Epilepsies of presumed genetic etiology show enrichment of rare variants that occur in the general population <br/> <br/>Author, co-author: Bundalian, Linnaeus; Su, Yin-Yuan; Chen, Siwei; Velluva, Akhil; Kirstein, Anna Sophia; Garten, Antje; Biskup, Saskia; Battke, Florian; Lal, Dennis; Heyne, Henrike O.; Platzer, Konrad; Lin, Chen-Ching; Lemke, Johannes R.; Duc, Diana Le; Krause, Roland; May, Patrick; Consortium, Epi <br/> <br/>Abstract: Previous studies suggested that severe epilepsies, e.g., developmental and epileptic encephalopathies (DEEs), are mainly caused by ultra-rare de novo genetic variants. For milder disease, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 control individuals. Here, we separately analyzed three different groups of epilepsies: severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in control individuals with an allele count R 1 and a minor allele frequency % 1:1,000, to be predicted as deleterious (CADD R 20), and to have an odds ratio in individuals with epilepsy R 2. We identified genes enriched with QRVs primarily in NAFE (n ¼ 72), followed by GGE (n ¼ 32) and DEE (n ¼ 21). This suggests that rare variants may play a more important role for causality of NAFE than for DEE. Moreover, we found that genes harboring QRVs, e.g., HSGP2, FLNA, or TNC, encode proteins that are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE that occur also in the general population, while in DEE and GGE, the contribution of such variants appears more limited. Fri, 30 Jun 2023 08:48:54 GMT http://hdl.handle.net/10993/55367 Title: Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson\textquoterights disease 2023.05.12.23289877 <br/> <br/>Author, co-author: Arena, Giuseppe; Landoulsi, Zied; Grossmann, Dajana; Vitali, Armelle; Delcambre, Sylvie; Baron, Alexandre; Antony, Paul; Boussaad, Ibrahim; Bobbili, Dheeraj Reddy; Sreelatha, Ashwin Ashok Kumar; Pavelka, Lukas; Klein, Christine; Seibler, Philip; Glaab, Enrico; Sharma, Manu; Krüger, Rejko; May, Patrick; Grünewald, Anne <br/> <br/>Abstract: Background Parkinson's disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ~10\% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration.Methods: To capture this mitochondria-related 'missing heritability', we leveraged on existing data from previous genome-wide association studies (GWAS) i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson\textquoterights Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls).Results: Applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk both in the Luxembourg Parkinson\textquoterights Study (odds ratio, OR=1.31[1.14-1.50], p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p=1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson's Study iPD patients stratified according to the OXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p < 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients.Conclusions: Our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden potentially eligible for future, more tailored mitochondrially targeted treatments. Sun, 18 Jun 2023 03:30:23 GMT http://hdl.handle.net/10993/55292 Title: Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias <br/> <br/>Author, co-author: Kaivola, Karri; Chia, Ruth; Ding, Jinhui; Rasheed, Memoona; Fujita, Masashi; Menon, Vilas; Walton, Ronald L.; Collins, Ryan L.; Billingsley, Kimberley; Brand, Harrison; Talkowski, Michael; Zhao, Xuefang; Dewan, Ramita; Stark, Ali; Ray, Anindita; Solaiman, Sultana; Alvarez Jerez, Pilar; Malik, Laksh; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Masellis, Mario; Keith, Julia; Black, Sandra E.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Topol, Eric; Torkamani, Ali; Tienari, Pentti; Foroud, Tatiana M.; Ghetti, Bernardino; Landers, John E.; Ryten, Mina; Morris, Huw R.; Hardy, John A.; Mazzini, Letizia; D'Alfonso, Sandra; Moglia, Cristina; Calvo, Andrea; Serrano, Geidy E.; Beach, Thomas G.; Ferman, Tanis; Graff-Radford, Neill R.; Boeve, Bradley F.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Chiò, Adriano; Bennett, David A.; De Jager, Philip L.; Ross, Owen A.; Dalgard, Clifton L.; Gibbs, J. Raphael; Traynor, Bryan J.; Scholz, Sonja W.; Soltis, Anthony R.; Viollet, Coralie; Sukumar, Gauthaman; Alba, Camille; Lott, Nathaniel; McGrath Martinez, Elisa; Tuck, Meila; Singh, Jatinder; Bacikova, Dagmar; Zhang, Xijun; Hupalo, Daniel N.; Adeleye, Adelani; Wilkerson, Matthew D.; Pollard, Harvey B.; Dalgard, Clifton L.; Black, Sandra E.; Gan-Or, Ziv; Keith, Julia; Masellis, Mario; Rogaeva, Ekaterina; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Calvo, Andrea; Canosa, Antonio; Chio, Adriano; Logroscino, Giancarlo; Mora, Gabriele; Krüger, Rejko; May, Patrick; Alcolea, Daniel; Clarimon, Jordi; Fortea, Juan; Gonzalez-Aramburu, Isabel; Infante, Jon; Lage, Carmen; Lleó, Alberto; Pastor, Pau; Sanchez-Juan, Pascual; Brett, Francesca; Aarsland, Dag; Al-Sarraj, Safa; Attems, Johannes; Gentleman, Steve; Hardy, John A.; Hodges, Angela K.; Love, Seth; McKeith, Ian G.; Morris, Christopher M.; Morris, Huw R.; Palmer, Laura; Pickering-Brown, Stuart; Ryten, Mina; Thomas, Alan J.; Troakes, Claire; Albert, Marilyn S.; Barrett, Matthew J.; Beach, Thomas G.; Bekris, Lynn M.; Bennett, David A.; Boeve, Bradley F.; Dalgard, Clifton L.; Dawson, Ted M.; Dickson, Dennis W.; Faber, Kelley; Ferman, Tanis; Ferrucci, Luigi; Flanagan, Margaret E.; Foroud, Tatiana M.; Ghetti, Bernardino; Gibbs, J. Raphael; Goate, Alison; Goldstein, David S.; Graff-Radford, Neill R.; Kaufmann, Horacio; Kukull, Walter A.; Leverenz, James B.; Lopez, Grisel; Mao, Qinwen; Masliah, Eliezer; Monuki, Edwin; Newell, Kathy L.; Palma, Jose-Alberto; Perkins, Matthew; Pletnikova, Olga; Renton, Alan E.; Resnick, Susan M.; Rosenthal, Liana S.; Ross, Owen A.; Scherzer, Clemens R.; Serrano, Geidy E.; Shakkottai, Vikram G.; Sidransky, Ellen; Tanaka, Toshiko; Tayebi, Nahid; Topol, Eric; Torkamani, Ali; Troncoso, Juan C.; Woltjer, Randy; Wszolek, Zbigniew K.; Scholz, Sonja W.; Baloh, Robert H.; Bowser, Robert; Brice, Alexis; Broach, James; Camu, William; Chiò, Adriano; Cooper-Knock, John; Drepper, Carsten; Drory, Vivian E.; Dunckley, Travis L.; Feldman, Eva; Fratta, Pietro; Gerhard, Glenn; Gibson, Summer B.; Glass, Jonathan D.; Hardy, John A.; Harms, Matthew B.; Heiman-Patterson, Terry D.; Jansson, Lilja; Kirby, Janine; Kwan, Justin; Laaksovirta, Hannu; Landers, John E.; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; MacGowan, Daniel J. L.; Maragakis, Nicholas J.; Mouzat, Kevin; Myllykangas, Liisa; Orrell, Richard W.; Ostrow, Lyle W.; Pamphlett, Roger; Pioro, Erik; Pulst, Stefan M.; Ravits, John M.; Robberecht, Wim; Rogaeva, Ekaterina; Rothstein, Jeffrey D.; Sendtner, Michael; Shaw, Pamela J.; Sidle, Katie C.; Simmons, Zachary; Stein, Thor; Stone, David J.; Tienari, Pentti J.; Traynor, Bryan J.; Troncoso, Juan C.; Valori, Miko; Van Damme, Philip; Van Deerlin, Vivianna M.; Van Den Bosch, Ludo; Zinman, Lorne <br/> <br/>Abstract: We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia. Wed, 07 Jun 2023 03:30:23 GMT http://hdl.handle.net/10993/55267 Title: Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers <br/> <br/>Author, co-author: Castelo Rueda, Maria Paulina; Zanon, Alessandra; Gilmozzi, Valentina; Lavdas, Alexandros; Raftopoulou, Athina; Delcambre, Sylvie; Del Greco, Fabiola; Klein, Christine; Grünewald, Anne; Pramstaller, Peter; Hicks, Andrew; Pichler, Irene <br/> <br/>Abstract: Homozygous or compound heterozygous (biallelic) variants in PRKN are causal for PD with highly penetrant symptom expression, while the much more common heterozygous variants may predispose to PD with highly reduced penetrance, through altered mitochondrial function. In the presence of pathogenic heterozygous variants, it is therefore important to test for mitochondrial alteration in cells derived from variant carriers to establish potential presymptomatic molecular markers. We generated lymphoblasts (LCLs) and human induced pluripotent stem cell (hiPSC)-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality. In LCLs, we detected hyperactive mitochondrial respiration, and, although milder compared to a biallelic PRKN-PD patient, hiPSC-derived neurons of non-manifesting heterozygous variant carriers also displayed several phenotypes of altered mitochondrial function. Overall, we identified molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase. Such markers might also be useful to identify individuals at greater risk of eventual disease development and for testing potential mitochondrial function-based neuroprotective therapies before neurodegeneration advances Thu, 01 Jun 2023 19:27:38 GMT http://hdl.handle.net/10993/55245 Title: Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort <br/> <br/>Author, co-author: Vollstedt, Eva-Juliane; Schaake, Susen; Lohmann, Katja; Padmanabhan, Shalini; Brice, Alexis; Lesage, Suzanne; Tesson, Christelle; Vidailhet, Marie; Wurster, Isabel; Hentati, Faycel; Mirelman, Anat; Giladi, Nir; Karen, Marder; Waters, Cheryl; Fahn, Stanley; Kasten, Meike; Brüggemann, Norbert; Borsche, Max; Foroud, Tatiana; Tolosa, Eduardo; Garrido, Alicia; Annesi, Grazia; Gagliardi, Monica; Bozi, Maria; Stefanis, Leonidas; Ferreira, Joaquim J.; Correia Guedes, Leonor; Avenali, Micol; Petrucci, Simona; Clark, Lorraine; Fedotova, Ekaterina Y.; Abramycheva, Natalya Y.; Alvarez, Victoria; Menéndez-González, Manuel; Jesús Maestre, Silvia; Gómez-Garre, Pilar; Mir, Pablo; Belin, Andrea Carmine; Ran, Caroline; Lin, Chin-Hsien; Kuo, Ming-Che; Crosiers, David; Wszolek, Zbigniew K.; Ross, Owen A.; Jankovic, Joseph; Nishioka, Kenya; Funayama, Manabu; Clarimon, Jordi; Williams-Gray, Caroline H.; Camacho, Marta; Cornejo-Olivas, Mario; Torres-Ramirez, Luis; Wu, Yih-Ru; Lee-Chen, Guey-Jen; Morgadinho, Ana; Pulkes, Teeratorn; Termsarasab, Pichet; Berg, Daniela; Gregor, Kuhlenbäumer; Kühn, Andrea A.; Borngräber, Friederike; de Michele, Giuseppe; De Rosa, Anna; Zimprich, Alexander; Puschmann, Andreas; Mellick, George D.; Jolanta, Dorszewska; Carr, Jonathan; Ferese, Rosangela; Stefano, Gambardella; Chase, Bruce; Markopoulou, Katerina; Wataru, Satake; Toda, Tatsushi; Rossi, Malco; Merello, Marcelo; Lynch, Timothy; Olszewska, Diana A.; Lim, Shen-Yang; Ahmad-Annuar, Azlina; Tan, Ai Huey; Al-Mubarak, Bashayer; Hanagasi, Hasmet; Koziorowski, Dariusz; Ertan, Sibel; Gen c, Gen Cer; de Carvalho Aguiar, Patricia; Barkhuizen, Melinda; Pimentel, Marcia M. G.; Saunders-Pullman, Rachel; van de Warrenburg, Bart; Bressman, Susan; Toft, Mathias; Appel-Cresswell, Silke; Lang, Anthony E.; Skorvanek, Matej; Boon, Agnita J. W.; Krüger, Rejko; Sammler, Esther M.; Tumas, Vitor; Zhang, Bao-Rong; Garraux, Gaetan; Chung, Sun Ju; Joong, Kim Yun; Winkelmann, Juliane; Sue, Carolyn M.; Eng-King, Tan; Damásio, Joana; Klivényi, Péter; Kostic, Vladimir S.; Arkadir, David; Martikainen, Mika; Borges, Vanderci; Hertz, Jens Michael; Brighina, Laura; Spitz, Mariana; Suchowersky, Oksana; Riess, Olaf; Parimal, Das; Mollenhauer, Brit; Gatto, Emilia M.; Skaalum, Petersen Maria; Wu, Ruey-Meei; Illarioshkin, Sergey N.; Valente, Enza Maria; Aasly, Jan O.; Aasly, Anna; N, Alcalay Roy; Thaler, Avner; Farrer, Matthew J.; Kathrin, Brockmann; Corvol, Jean-Christophe; Klein, Christine; Aasly, Anna; Aasly, Jan O.; Abramycheva, Natalya Y.; Ahmad-Annuar, Azlina; Albanese, Alberto; Alcalay, Roy N.; Aldakheel, Amaal; Alkhairallah, Thamer; Bashayer, Al-Mubarak; Al-Tassan, Nada; Alvarez, Victoria; Paolo, Amami; Annesi, Grazia; Appel-Cresswell, Silke; Araujo, Leite Marco Antonio; Arkadir, David; Avenali, Micol; Ferraz, Henrique Ballalai; Bardien, Soraya; Melinda, Barkhuizen; Barrett, Matthew J.; Ba sak, A. Nazl I; Berg, Daniela; Bilgic, Basar; Bloem, Bastiaan R.; Bonifati, Vincenzo; Boon, Agnita J. W.; Borges, Vanderci; Borngräber, Friederike; Borsche, Max; Bozi, Maria; Bressman, Susan; Brice, Alexis; Brighina, Laura; Brockmann, Kathrin; Brüggemann, Norbert; Camacho, Marta; Belin, Andrea Carmine; Carr, Jonathan; Cesarini, Martin Emiliano; Cornejo-Olivas, Mario; Chase, Bruce; Ju, Chung Sun; Guedes, Leonor Correia; Clarimon, Jordi; Lorraine, Clark; Corvol, Jean-Christophe; Crosiers, David; Parimal, Das; de Carvalho Aguiar, Patricia; Damásio, Joana; de Michele, Giuseppe; De Rosa, Anna; Dieguez, Elena; Dorszewska, Jolanta; Ertan, Sibel; Fahn, Stanley; Farrer, Matthew J.; Fedotova, Ekaterina Y.; Ferese, Rosangela; Ferreira, Joaquim J.; Foroud, Tatiana; Funayama, Manabu; Fung, Victor S. C.; Gagliardi, Monica; Stefano, Gambardella; Garraux, Gaetan; Garrido, Alicia; Gatto, Emilia M.; Gen c, Gen Cer; Giladi, Nir; Pilar, Gómez-Garre; Hanagasi, Hasmet; Hattori, Nobutaka; Faycel, Hentati; Hertz, Jens Michael; Illarioshkin, Sergey N.; Jankovic, Joseph; Januario, Cristina; Maestre, Silvia Jesús; Kaasinen, Valtteri; Kasten, Meike; Hiroshi, Kataoka; Kievit, Anneke A.; Kim, Yun Joong; Christine, Klein; Klivényi, Péter; Kostic, Vladimir S.; Koziorowski, Dariusz; Krüger, Rejko; Kühn, Andrea A.; Kuhlenbäumer, Gregor; Kuo, Ming-Che; Lang, Anthony E.; Lee-Chen, Guey-Jen; Lesage, Suzanne; Lim, Jia Lun; Lim, Shen-Yang; Lin, Chin-Hsien; Lohmann, Katja; Timothy, Lynch; Marder, Karen; Markopoulou, Katerina; Martikainen, Mika; May, Patrick; McCarthy, Allan; Mellick, George D.; Menéndez-González, Manuel; Merello, Marcelo; Mir, Pablo; Mirelman, Anat; Mollenhauer, Brit; Briceno, Hugo Morales; Morgadinho, Ana; Morris, Huw; Mosejova, Alexandra; Nishioka, Kenya; Cakmak, Özgür Öztop; Olszewska, Diana A.; Orr-Urtreger, Avi; Pachchek, Sinthuja; Padmanabhan, Shalini; Periñ\'an, Maria Teresa; Petrucci, Simona; Pimentel, Marcia M. G.; Procopio, Radha; Pulkes, Teeratorn; Puschmann, Andreas; Ran, Caroline; Riess, Olaf; Ross, Owen A.; Rossi, Malco; Ruiz-Martinez, Javier; Sammler, Esther M.; Pereira, João Santos; Satake, Wataru; Saunders-Pullman, Rachel; Schaake, Susen; Skaalum, Petersen Maria; Skorvanek, Matej; Stefanis, Leonidas; Soto-Beasley, Alexandra I.; Sousa, Mário; Spitz, Mariana; Suchowersky, Oksana; Sue, Carolyn M.; Tan, Ai Huey; Tan, Eng-King; Thaler, Avner; Tepge c, Fatih; Termsarasab, Pichet; Tesson, Christelle; Toda, Tatsushi; Toft, Mathias; Tolosa, Eduardo; Torres-Ramirez, Luis; Tumas, Vitor; Uyguner, Oya; Valente, Enza Maria; van de Warrenburg, Bart; Vidailhet, Marie; Vollstedt, Eva-Juliane; Walton, Ronald L.; Waters, Cheryl; H, Williams-Gray Caroline; Winkelmann, Juliane; Wu, Yih-Ru; Isabel, Wurster; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Bao-Rong, Zhang; Zimprich, Alexander <br/> <br/>Abstract: BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Tue, 30 May 2023 03:30:26 GMT