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Article Dans Une Revue Nature Année : 2024

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

Silvia Ronchi
  • Fonction : Auteur
Zuzanna Maniecka
  • Fonction : Auteur
Eva-Maria Hock
  • Fonction : Auteur
Elena Tantardini
Sonu Sahadevan
  • Fonction : Auteur
Vanessa Hoop
  • Fonction : Auteur
Igor Delvendahl
Manuela Pérez-Berlanga
Alexander van der Bourg
  • Fonction : Auteur
Dasa Bohaciakova
Puneet Sharma
Laura de Vos
Karl Frontzek
Adriano Aguzzi
Tammaryn Lashley
Mark D Robinson
  • Fonction : Auteur
Theofanis Karayannis
Martin Mueller
Andreas Hierlemann

Résumé

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 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.
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Dates et versions

hal-04466545 , version 1 (19-02-2024)

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Marian Hruska-Plochan, Vera I Wiersma, Katharina M Betz, Izaskun Mallona, Silvia Ronchi, et al.. A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature, In press, ⟨10.1038/s41586-024-07042-7⟩. ⟨hal-04466545⟩

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