A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F24%3A00139443" target="_blank" >RIV/00216224:14110/24:00139443 - isvavai.cz</a>
Result on the web
<a href="https://www.nature.com/articles/s41586-024-07042-7" target="_blank" >https://www.nature.com/articles/s41586-024-07042-7</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41586-024-07042-7" target="_blank" >10.1038/s41586-024-07042-7</a>
Alternative languages
Result language
angličtina
Original language name
A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
Original language 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10601 - Cell biology
Result continuities
Project
<a href="/en/project/GJ18-25429Y" target="_blank" >GJ18-25429Y: Functional studies of miRNAs and protein-coding genes involved in stem cell-specification during neural development.</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Nature
ISSN
0028-0836
e-ISSN
1476-4687
Volume of the periodical
626
Issue of the periodical within the volume
8001
Country of publishing house
DE - GERMANY
Number of pages
45
Pages from-to
1-45
UT code for WoS article
001183983000018
EID of the result in the Scopus database
2-s2.0-85185117248