Year: 2021
Type: preprint
Abstract: Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating these age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies 1,2 , which involve human-specific mechanisms 3–6 that cannot be directly studied in animal models. To explore the emergence and consequences of TDP-43 pathologies, we generated iPSC-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors 7 . Single-cell transcriptomics (scRNA-seq) and comparison to independent NSCs 8 , showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks. Neuronal and glial maturation in iCoMoNSC-derived cultures was similar to that of cortical organoids 9 . Overexpression of wild-type TDP-43 in a minority of iCoMoNSC-derived neurons led to progressive fragmentation and aggregation, resulting in loss of function and neurotoxicity. scRNA-seq revealed a novel set of misregulated RNA targets coinciding in both TDP-43 overexpressing neurons and patient brains exhibiting loss of nuclear TDP-43. The strongest misregulated target encoded for the synaptic protein NPTX2, which was consistently misaccumulated in ALS and FTLD patient neurons with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby highlighting a new pathway of neurotoxicity.
Authors: Marian Hruska-Plochan, Katharina M. Betz, Silvia Ronchi, Vera I. Wiersma, Zuzanna Maniecka, Eva-Maria Hock, Florent Laferriere, Sonu Sahadevan, Vanessa Hoop, Igor Delvendahl, Martina Panatta, Alexander van der Bourg, Dasa Bohaciakova, Karl Frontzek, Adriano Aguzzi, Tammaryn Lashley, Mark D. Robinson, Theofanis Karayannis, Martin Mueller, Andreas Hierlemann, Magdalini Polymenidou
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, ALS Association, Stiftung für die Erforschung der Muskelkrankheiten, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Grantová Agentura České Republiky, Universität Zürich, Georges and Antoine Claraz Foundation, Functional Genomics Center Zurich, Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London, H2020 European Research Council
Awards: HD-MEA-based Neuronal Assays and Network Analysis for Phenotypic Drug Screenings, Deciphering the mechanisms of TDP-43 neurotoxicity in novel human neuronal systems, Deciphering the pathogenic mechanisms of C9ORF72 dipeptide proteins, Functional studies of miRNAs and protein-coding genes involved in stem cell-specification during neural development., Exploring the molecular basis of disease heterogeneity in TDP-43 proteinopathies, G7426642301, Microtechnology and integrated microsystems to investigate neuronal networks across scales
OpenAlex ID: W4200169539