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

Varování

Publikace nespadá pod Pedagogickou fakultu, ale pod Lékařskou fakultu. Oficiální stránka publikace je na webu muni.cz.

Autoři	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
Rok publikování	2024
Druh	Článek v odborném periodiku
Časopis / Zdroj	Nature
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.nature.com/articles/s41586-024-07042-7
Doi	http://dx.doi.org/10.1038/s41586-024-07042-7
Klíčová slova	human neural networks; model; ALS; FTLD; NPTX2 pathology
Popis	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.
Související projekty:	Funkční studie mikroRNA u nerálních kmenových buněk v průběhu diferenciace