Citations 4
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.
C9orf72 Repeat Expansion Induces Metabolic Dysfunction in Human iPSC ‐Derived Microglia and Modulates Glial‐Neuronal Crosstalk
Mearelli, Marika , Hirschberg, Insa, Dubroux, Malvina, Provenzano, Francesca , Rizzuti, Mafalda , Sheth, Udit , Deleidi, Michela , Weissleder, Christin , Sheth, Udit , Deleidi, Michela , Weissleder, Christin , Giachino, Carmela , J., Maria Jose Perez , Ottoboni, Linda , Gendron, Tania F. , Corti, Stefania Paola
Glia | September 1, 2025 | Volume: 74 | Issue: 1 | Pages: No page available
ABSTRACT The C9orf72 hexanucleotide repeat expansion mutation is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but its cell type‐specific effects on energy metabolism and immune pathways remain poorly understood. Using induced pluripotent stem cell (iPSC)‐derived motor neurons, astrocytes, and microglia from C9orf72 patients and their isogenic controls, we investigated metabolic changes at the single‐cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While C9orf72 motor neurons exhibited impaired mitochondrial respiration and reduced ATP production, C9orf72 microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC‐derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia‐driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.
Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis
Johnson, Janel O., Chia, Ruth , Miller, Danny E. , Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada F. , Topp, Simon , Gibbs, J. Raphael , Cookson, Mark , Sabir, Marya S. , Dalgard, Clifton L. , Troakes, Claire , Jones, Ashley R., Shatunov, Aleksey , Iacoangeli, Alfredo , Khleifat, Ahmad Al , Ticozzi, Nicola , Gellera, Cinzia , Blair, Ian P. , Dobson‐Stone, Carol , Bonkowski, Emily , Palvadeau, Robin , Tienari, Pentti J. , Morrison, Karen , Shaw, Pamela J. , Brown, Robert H., Calvo, Andrea, Al-Saif, Hind, Leigh, Fawn, Chang, Irene J. , Perlman, Seth J. , Scott, Anna I. , Başak, A. Nazlı , Landers, John E. , Crawford, Thomas O. , Smith, Bradley , Traynor, Bryan J. , Gkazi, Athina Soragia, Kenna, Kevin P., Keagle, Pamela, Tiloca, Cinzia , Vance, Caroline , King, Andrew , Pensato, Viviana , Castellotti, Barbara , Baas, Frank , Asbroek, Anneloor L.M.A. ten , McKenna‐Yasek, Diane, McLaughlin, Russell L. , Polak, Meraida , Asress, Seneshaw, Stević, Zorica, D’Alfonso, Sandra , Mazzini, Letizia, Bo, Roberto Del, Gagliardi, Stella , Querin, Giorgia, Bertolin, Cinzia , Rademakers, Rosa, Blitterswijk, Marka van , Lauria, Giuseppe, Corrado, Lucia , Sorarú, Gianni , Williams, Kelly L. , Leblond-Manry, Claire, Hardiman, Orla , Berg, Leonard H. van den, Pall, Hardev, Taroni, Franco , Wu, Zheyang , Glass, Jonathan D., Ratti, Antonia, Adeleye, Adelani, Alba, Camille , Viollet, Coralie , Bačíková, Dagmar, Hupalo, Daniel N., Pollard, Harvey B. , Martinez, Elisa McGrath, Ahmed, Sarah , Arepalli, Sampath, Baloh, Robert H. , Bowser, Robert , Campbell, Roy H. , Camu, William, Cooper‐Knock, Johnathan , Ding, Jinhui, Drory, Vivian E., Dunckley, Travis , Eicher, John D., England, Bryce, Faghri, Faraz , Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro , Geiger, Joshua T. , Gibson, Summer, Hardy, John , Harms, Matthew , Heiman‐Patterson, Terry , Hernandez, Dena G., Jansson, Lilja, Kowall, Neil W. , Laaksovirta, Hannu , Landi, Francesco , Ber, Isabelle Le , Lumbroso, Serge , MacGowan, Daniel J., Maragakis, Nicholas J., Mouzat, Kévin , Murphy, Natalie A., Myllykangas, Liisa , Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pickering‐Brown, Stuart , Pioro, Erik P., Pletniková, Olga , Ravits, John , Rivera, Alberto , Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D., Scholz, Sonja W. , Sendtner, Michael , Sidle, Katie, Singleton, Andrew, Smith, Nathan, Stone, David J. , Troncoso, Juan C., Valori, Miko , Damme, Philip Van , Deerlin, Vivianna M Van, Bosch, Ludo Van Den , Zinman, Lorne, Landers, John E., Chiò, Adriano, Angelocola, Stefania, Ausiello, Francesco P., Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bisogni, Giulia , Borghero, Giuseppe , Brunetti, Maura, Canale, Fabrizio , Canosa, Antonio, Cantisani, Teresa A., Cardinali, Patrizio, Casale, Federico , Colletti, Tiziana , Conforti, F. L. , Conte, Amelia , Conti, Elisa, Corbo, Massimo , Cuccu, Stefania, D’Errico, Eustachio , Marco, Giovanni De , Dubbioso, Raffaele, Ferrarese, Carlo , Ferraro, Pilar M. , Floris, Gianluca , Fuda, Giuseppe, Gallone, Salvatore , Gianferrari, Giulia , Giannini, Fabio, Grassano, Maurizio, Greco, Lucia Catherine , Iazzolino, Barbara, Introna, Alessandro , Logroscino, Giancarlo , Logullo, Francesco, Lunetta, Christian , Mandich, Paola , Mandrioli, Jessica , Manera, Umberto , Manganelli, Fiore, Martinelli, Ilaria , Moglia, Cristina, Mosca, Lorena, Murru, Maria Rita, Origone, Paola , Petrelli, Cristina, Pozzi, Susanna, Pugliatti, Maura , Ricci, Claudia , Riolo, Giulia , Russo, Massimo, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo , Simonini, Cecilia , Tanel, Raffaella , Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio , Vasta, Rosario , Vacchiano, Veria, Volanti, Paolo , Zollino, Marcella , Lauria, Giuseppe , Ratti, Antonia , Ostrow, Lyle W. , Fratta, Pietro , Chia, Ruth , Logroscino, Giancarlo , van Blitterswijk, Marka , Scholz, Sonja W , Van Den Bosch, Ludo , Van Damme, Philip , Hardy, John , Fratta, Pietro , Fratta, Pietro , Troakes, Claire , Hardiman, Orla , Dalgard, Clifton L , Myllykangas, Liisa , Li, Rachel , Renton, Alan , Jones, Ashley R., Silani, Vincenzo , Kwok, John B. , Al‐Chalabi, Ammar , Calvo, Andrea , Mora, Gabriele , Gotkine, Marc , Glass, Ian A. , Shaw, Christopher E. , Chiò, Adriano , Fallini, Claudia , Gkazi, Soragia Athina , Scotter, Emma L. , Kenna, Kevin Patrick , Keagle, Pamela , Colombrita, Claudia , Asress, Seneshaw, Esteban‐Pérez, Jesús , Mazzini, Letizia , Comi, Giacomo P. , Ceroni, Mauro , Rheenen, Wouter van , Rademakers, Rosa , Duga, Stefano , Corti, Stefania Paola , Cereda, Cristina , Nicholson, Garth A. , Rouleau, Guy Armand , Veldink, Jan H. , Berg, Leonard H. van den , Turner, Martin R. , Talbot, Kevin , García‐Redondo, Alberto , Adeleye, Adelani, Soltis, Anthony R. , Sukumar, Gauthaman , Wilkerson, Matthew D. , Brady, Christopher B. , Brice, Alexis , Broach, James R , Campbell, Roy H., Ding, Jinhui , Drepper, Carsten , Gerhard, Glenn S. , Harms, Matthew B. , Hernandez, Dena G., Kirby, Janine , Landeck, Natalie , Maragakis, Nicholas J. , Pamphlett, Roger , Pliner, Hannah A. , Pulst, Stefan M. , Rothstein, Jeffrey D. , Simmons, Zachary , Singleton, Andrew , Smith, Nathan, Troncoso, Juan C. , Deerlin, Vivianna M. Van , Zinman, Lorne , Ausiello, Francesco Pio, Barberis, Marco , Battistini, Stefania , Bersano, Enrica , Brunetti, Maura , Cabona, Corrado , Canosa, Antonio , Capasso, Margherita , Caponnetto, Claudia , Carrera, Paola , Bella, Eleonora Dalla , Dubbioso, Raffaele , Filippi, Massimo , Fini, Nicola , Grassano, Maurizio , Iazzolino, Barbara, Bella, Vincenzo La , Lattante, Serena , Liguori, Rocco , Manganelli, Fiore , Marangi, Giuseppe , Marinou, Kalliopi , Marrosu, Maria Giovanna , Messina, Sonia , Moglia, Cristina , Mosca, Lorena, Passaniti, Carla , Petrucci, Antonio , Quattrini, Angelo , Riva, Nilo , Russo, Massimo, Sabatelli, Mario , Salamone, Paolina , Simone, Isabella Laura , Spataro, Rossella , Tedeschi, Gioacchino , Trojsi, Francesca , Vacchiano, Veria , Vita, Giuseppe , Zucchi, Elisabetta
JAMA Neurology | August 30, 2021 | Volume: 78 | Issue: 10 | Pages: 1236
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.