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A model of human neural networks reveals NPTX2 pathology in ALS and FTLD by Marian Hruska-Plochan; Vera I. Wiersma; Katharina M. Betz; Izaskun Mallona; Silvia Ronchi; Zuzanna Maniecka; Eva-Maria Hock; Elena Tantardini; Florent Laferriere; Sonu Sahadevan; Vanessa Hoop; Igor Delvendahl; Manuela Pérez-Berlanga; Beatrice Gatta; Martina Panatta; Alexander van der Bourg; Dasa Bohaciakova; Puneet Sharma; Laura De Vos; Karl Frontzek; Adriano Aguzzi; Tammaryn Lashley; Mark D. Robinson; Theofanis Karayannis; Martin Mueller; Andreas Hierlemann; Magdalini Polymenidou is a Physics and Astronomy article available to read on EtoBox.

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Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies^1^, which involve human-specific mechanisms^2–5^ that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors^6^. Single-cell transcriptomics and comparison to independent neural stem cells^7^ 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 (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids^8^. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomic

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Author

Marian Hruska-Plochan; Vera I. Wiersma; Katharina M. Betz; Izaskun Mallona; Silvia Ronchi; Zuzanna Maniecka; Eva-Maria Hock; Elena Tantardini; Florent Laferriere; Sonu Sahadevan; Vanessa Hoop; Igor Delvendahl; Manuela Pérez-Berlanga; Beatrice Gatta; Martina Panatta; Alexander van der Bourg; Dasa Bohaciakova; Puneet Sharma; Laura De Vos; Karl Frontzek; Adriano Aguzzi; Tammaryn Lashley; Mark D. Robinson; Theofanis Karayannis; Martin Mueller; Andreas Hierlemann; Magdalini Polymenidou

Publisher

Nature Publishing Group UK

Published

2024

Language

EN

Field

Physics and Astronomy (Physical Sciences)