Pasterkamp, R. Jeroen
Mayo Clinic
University Medical Center Utrecht
Citations 2
Multi-omics of C9orf72 spinal cord organoids reveal convergent molecular signatures and targets
Galli, Noemi, Galvani, Giorgia, Brambilla, Lorenzo, Sebastiani, E., Bo, Roberto Del, Sheth, Udit, Gendron, Tanya, Ottoboni, Linda, Corti, Stefania, Rizzuti, Mafalda , Brambilla, Lorenzo, Ripolone, Michela , Napoli, Laura , Maeda, Akihiro , Bolli, Niccolò , Sheth, Udit , Pasterkamp, R. Jeroen , Ottoboni, Linda , Corti, Stefania Paola
No container title available | July 8, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background: amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease, characterised by the progressive degeneration of upper and lower motor neurons in the brain and spinal cord. Despite substantial advances in the understanding of underlying disease mechanisms, effective therapies remain lacking. Methods: we generated spinal cord organoids from patient-derived induced pluripotent stem cells and matched isogenic controls to model in vitro the molecular pathology associated with the hexanucleotide repeat expansion within the C9orf72 gene. Results: C9orf72 organoids displayed delayed neuronal maturation, axonal degeneration, mitochondrial abnormalities, enhanced apoptotic signaling, and accumulation of dipeptide repeat proteins. Integrated multi-omics analyses revealed a consistent down-regulation of Netrin-1 at both the transcript and protein levels across patient-derived organoids, suggesting that its loss may contribute to impaired neuronal connectivity, compromised axonal integrity, and increased motor neuron vulnerability in C9orf72 amyotrophic lateral sclerosis. Conclusions: together, these findings establish patient-derived spinal cord organoids as a biologically relevant and in vitro model that recapitulates key cellular and molecular hallmarks of C9orf72-associated amyotrophic lateral sclerosis. This platform provides a valuable framework to deepen disease mechanisms, toward the development of new effective therapeutic strategies.
Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
Rheenen, Wouter van , Spek, Rick van der, Berg, Leonard van den, Hop, Paul , Zwamborn, Ramona, Klein, Niek de , Westra, Harm-Jan , Bakker, Olivier, Shireby, Gemma , Dolzhenko, Egor, Dekker, Annelot, Westeneng, Henk-Jan, Tazelaar, Gijs, Eijk, Kristel van , Kooyman, Maarten , Doherty, Mark, Iacoangeli, Alfredo, Cooper‐Knock, Johnathan , Smith, Bradley , Chandran, Siddharthan , Morrison, Karen, Shaw, Pamela, Hardy, John , Orrell, Richard, Basak, Nazli, Ratti, Antonia, Pinter, Guiseppe Lauria, D'Alfonso, Sandra, Soraru, Gianni, Padovani, Alessandro , Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Nefussy, Beatrice, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Baloh, Robert, Bell, Shaugn, Vourc'h, Patrick, Corcia, Philippe, Couratier, Philippe, Meininger, Vincent, Salachas, Francois, Pardina, Jesús Mora, Assialioui, Abdelilah , Rojas‐García, Ricardo , Dion, Patrick, Ludolph, Albert, Weishaupt, Jochen, Brenner, David, Freischmidt, Axel , Bensimon, Gilbert , Durr, Alexandra, Payan, Christine, Saker-Delye, Safa, Wood, Nicholas , Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Braun, Alice, Hofman, Albert, Cichon, Sven , Traynor, Bryan, Singleton, Andrew, Neto, Miguel Mitne, Ophoff, Roel, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Rödiger, Annekathrin, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Berjamin, Stubendorff, Beatrice, Witte, Otto W. , Hübner, Christian, Graff, Caroline , Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia , Koritnik, Blaž , Zidar, Janez , Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Mónica, Henderson, Robert , Furlong, Sarah , McCombe, Pamela, Ngo, Shyuan, Steyn, Frederik, Mather, Karen A. , Sachdev, Perminder S. , Henders, Anjali, Carvalho, Mamede de, Petri, Susanne, Weber, Markus , Glass, Jonathan D. , Brown, Robert, Landers, John, Garton, Fleur, McRae, Allan, Mill, Jonathan , Kenna, Kevin, Runz, Heiko, Franke, Lude , Damme, Philip Van , Gaur, Nayana , Steyn, Frederik J. , Landers, John E. , Westra, Harm-Jan , Steyn, F J , Cichon, Sven , Sachdev, Perminder S , Van Damme, Philip , Hardy, John , Padovani, Alessandro , Graff, Caroline , Spek, Rick A. A. van der , Bakker, Mark K. , Veldink, Jan H. , Vugt, Joke J.F.A. van , Zwamborn, Ramona A.J. , Deelen, Patrick , Hannon, Eilís , Moisse, Matthieu , Baird, Denis A. , Restuadi, Restuadi , Gawor, Klara , Westeneng, Henk‐Jan , Byrne, Ross Patrick , Heverin, Mark , Khleifat, Ahmad Al , Iacoangeli, Alfredo , Shatunov, Aleksey , Ticozzi, Nicola , Gromicho, Marta , Pal, Suvankar , Orrell, Richard W., Sendtner, Michael , Meyer, Thomas , Basak, Nazli A., Kooi, Anneke J. van der , Ratti, Antonia , Fogh, Isabella , Gellera, Cinzia , Corti, Stefania Paola , Cereda, Cristina , Sproviero, Daisy , D’Alfonso, Sandra , Siciliano, Gabriele , Filosto, Massimiliano , Chiò, Adriano , Calvo, Andrea , Moglia, Cristina , Brunetti, Maura , Canosa, Antonio , Grassano, Maurizio , Beghi, Ettore , Pupillo, Elisabetta , Logroscino, Giancarlo , Osmanovic, Alma , Nordin, Angelica , Lerner, Yossef, Zabari, Michal, Gotkine, Marc , Vourc’h, Patrick , Corcia, Philippe , Couratier, Philippe , Millecamps, Stéphanie , Meininger, Vincent, Salachas, François, Ross, Jay P. , Ludolph, Albert, Brice, Alexis , Dürr, Alexandra , Saker-Delye, Safaa, Wood, Nicholas , Topp, Simon , Rademakers, Rosa , Tittmann, Lukas , Franke, André , Ripke, Stephan , Braun, Alice , Kraft, Julia , Whiteman, David C. , Olsen, Catherine M. , Uitterlinden, André G. , Hofman, Albert, Rietschel, Marcella , Nöthen, Markus M. , Amouyel, Philippe , Traynor, Bryan J. , Singleton, Andrew, Cauchi, Ruben J. , Ophoff, Roel A. , Lomen‐Hoerth, Catherine , Deerlin, Vivianna M. Van , Großkreutz, Julian , Rödiger, Annekathrin, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Steinbach, Robert , Hübner, Christian, Fominykh, Vera , Demeshonok, Vera, Rogelj, Boris , Drory, Vivian, Blair, Ian P. , Kiernan, Matthew C. , Benyamin, Beben , Mathers, Susan , Needham, Merrilee , Ngo, Shyuan T. , Nicholson, Garth A. , Pamphlett, Roger , Rowe, Dominic B. , Williams, Kelly L. , Wallace, Leanne M. , Carvalho, Mamede A. de , Pinto, Susana , Petri, Susanne , Rouleau, Guy Armand , Silani, Vincenzo , Curtis, Charles J. C. , Breen, Gerome , Brown, Robert, Shaw, Christopher E. , Andersen, Peter Munch , Groen, Ewout J. N. , Es, Michael A. van , Pasterkamp, R. Jeroen , Fan, Dongsheng , Smith, George Davey , Gaunt, Tom R. , Eberle, Michael A. , McLaughlin, Russell L. , Hardiman, Orla , Wray, Naomi , Tsai, Ellen A. , Runz, Heiko , Al‐Chalabi, Ammar
No container title available | March 18, 2021 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.