A model of human neural networks reveals NPTX2 pathology in ALS and FTLD

• 成果类型: Article
• 署名作者: Hruska-Plochan, Marian; Wiersma, Vera I.; Betz, Katharina M.; Mallona, Izaskun; Ronchi, Silvia; Maniecka, Zuzanna; Hock, Eva-Maria; Tantardini, Elena; Laferriere, Florent; Sahadevan, Sonu; Hoop, Vanessa; Delvendahl, Igor; Perez-Berlanga, Manuela; Gatta, Beatrice; Panatta, Martina; van der Bourg, Alexander; Bohaciakova, Dasa; Sharma, Puneet; De Vos, Laura; Frontzek, Karl; Aguzzi, Adriano; Lashley, Tammaryn; Robinson, Mark D.; Karayannis, Theofanis; Mueller, Martin; Hierlemann, Andreas; Polymenidou, Magdalini
• 署名单位: University of Zurich; University of Zurich; Swiss Institute of Bioinformatics; University of Zurich; University of Zurich; Masaryk University; University of Bern; University of Zurich; University of London; University College London; University of London; University College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6310
• DOI: 10.1038/s41586-024-07042-7
• 发表日期: 2024-02-29
• 关键词: frontotemporal lobar degeneration; neuronal pentraxin; excitatory synapses; rna; tdp-43; disease; narp; protein; aggregation; mutations

摘要

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 proteinopathies1, which involve human-specific mechanisms2-5 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 precursors6. Single-cell transcriptomics and comparison to independent neural stem cells7 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 organoids8. 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 transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3 ' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity. A neural stem cell culture system derived from induced pluripotent stem cells forms a network of synaptically connected and electrophysiologically active neurons that were used as a model system to identify a mechanism of TDP-43-induced neurodegeneration.