| Citation |
HRUSKA-PLOCHAN, Marian, 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 PEREZ-BERLANGA, Beatrice
GATTA, Martina PANATTA, van der Bourg ALEXANDER, Dáša
BOHAČIAKOVÁ, Puneet SHARMA, De Vos LAURA, Karl FRONTZEK,
Adriano AGUZZI, Tammaryn LASHLEY, Mark D ROBINSON, Theofanis
KARAYANNIS, Martin MUELLER, Andreas HIERLEMANN and Magdalini
POLYMENIDOU. A model of human neural networks reveals NPTX2
pathology in ALS and FTLD. Nature. BERLIN: NATURE PORTFOLIO,
2024, vol. 626, No 8001, p. 1-45. ISSN 0028-0836. Available
from: https://dx.doi.org/10.1038/s41586-024-07042-7. |
| Description |
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.
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