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

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 Bourg, Dasa Bohaciakova, Puneet Sharma, Laura Vos, Karl Frontzek, Adriano Aguzzi, Tammaryn Lashley, Mark D. Robinson, Theofanis Karayannis, Martin Mueller, Andreas Hierlemann and Magdalini Polymenidou ()
Additional contact information
Marian Hruska-Plochan: University of Zurich
Vera I. Wiersma: University of Zurich
Katharina M. Betz: University of Zurich
Izaskun Mallona: University of Zurich
Silvia Ronchi: ETH Zürich
Zuzanna Maniecka: University of Zurich
Eva-Maria Hock: University of Zurich
Elena Tantardini: University of Zurich
Florent Laferriere: University of Zurich
Sonu Sahadevan: University of Zurich
Vanessa Hoop: University of Zurich
Igor Delvendahl: University of Zurich
Manuela Pérez-Berlanga: University of Zurich
Beatrice Gatta: University of Zurich
Martina Panatta: University of Zurich
Alexander Bourg: University of Zurich
Dasa Bohaciakova: Masaryk University Brno
Puneet Sharma: University of Bern
Laura Vos: University of Zurich
Karl Frontzek: University of Zurich
Adriano Aguzzi: University of Zurich
Tammaryn Lashley: UCL Institute of Neurology
Mark D. Robinson: University of Zurich
Theofanis Karayannis: University of Zurich
Martin Mueller: University of Zurich
Andreas Hierlemann: ETH Zürich
Magdalini Polymenidou: University of Zurich

Nature, 2024, vol. 626, issue 8001, 1073-1083

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07042-7

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