| 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. |
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@article{2409566,
author = {HruskaandPlochan, Marian and Wiersma, Vera I and Betz, Katharina M and Mallona, Izaskun and Ronchi, Silvia and Maniecka, Zuzanna and Hock, EvaandMaria and Tantardini, Elena and Laferriere, Florent and Sahadevan, Sonu and Hoop, Vanessa and Delvendahl, Igor and PerezandBerlanga, Manuela and Gatta, Beatrice and Panatta, Martina and Alexander, van der Bourg and Bohačiaková, Dáša and Sharma, Puneet and Laura, De Vos and Frontzek, Karl and Aguzzi, Adriano and Lashley, Tammaryn and Robinson, Mark D and Karayannis, Theofanis and Mueller, Martin and Hierlemann, Andreas and Polymenidou, Magdalini},
article_location = {BERLIN},
article_number = {8001},
doi = {http://dx.doi.org/10.1038/s41586-024-07042-7},
keywords = {human neural networks; model; ALS; FTLD; NPTX2 pathology},
language = {eng},
issn = {0028-0836},
journal = {Nature},
title = {A model of human neural networks reveals NPTX2 pathology in ALS and FTLD},
url = {https://www.nature.com/articles/s41586-024-07042-7},
volume = {626},
year = {2024}
}
TY - JOUR
ID - 2409566
AU - 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 - Alexander, van der Bourg - Bohačiaková, Dáša - Sharma, Puneet - Laura, De Vos - Frontzek, Karl - Aguzzi, Adriano - Lashley, Tammaryn - Robinson, Mark D - Karayannis, Theofanis - Mueller, Martin - Hierlemann, Andreas - Polymenidou, Magdalini
PY - 2024
TI - A model of human neural networks reveals NPTX2 pathology in ALS and FTLD
JF - Nature
VL - 626
IS - 8001
SP - 1-45
EP - 1-45
PB - NATURE PORTFOLIO
SN - 00280836
KW - human neural networks
KW - model
KW - ALS
KW - FTLD
KW - NPTX2 pathology
UR - https://www.nature.com/articles/s41586-024-07042-7
N2 - 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.
ER -
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. \textit{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.
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