J 2024

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

HRUSKA-PLOCHAN, Marian, Vera I WIERSMA, Katharina M BETZ, Izaskun MALLONA, Silvia RONCHI et. al.

Základní údaje

Originální název

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

Autoři

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 (703 Slovensko, domácí), Puneet SHARMA, De Vos LAURA, Karl FRONTZEK, Adriano AGUZZI, Tammaryn LASHLEY, Mark D ROBINSON, Theofanis KARAYANNIS, Martin MUELLER, Andreas HIERLEMANN a Magdalini POLYMENIDOU

Vydání

Nature, BERLIN, NATURE PORTFOLIO, 2024, 0028-0836

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

Impakt faktor

Impact factor: 64.800 v roce 2022

Organizační jednotka

Lékařská fakulta

UT WoS

001183983000018

Klíčová slova anglicky

human neural networks; model; ALS; FTLD; NPTX2 pathology

Štítky

Příznaky

Mezinárodní význam, Recenzováno
Změněno: 10. 6. 2024 14:23, Mgr. Tereza Miškechová

Anotace

V originále

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.

Návaznosti

GJ18-25429Y, projekt VaV
Název: Funkční studie mikroRNA u nerálních kmenových buněk v průběhu diferenciace
Investor: Grantová agentura ČR, Funkční studie mikroRNA u nerálních kmenových buněk v průběhu diferenciace