Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD

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
. 2021-12-09; :
DOI: 10.1101/2021.12.08.471089

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 proteinopathies1,2, which involve human-specific mechanisms3–6 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 precursors7. Single-cell transcriptomics (scRNA-seq) and comparison to independent NSCs8, 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 organoids9. 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.

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