{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["27(3)"],"submitter":["Lepine S"],"pubmed_abstract":["Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in <i>TARDBP</i> (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR-Cas9, we engineered two homozygous knock-in induced pluripotent stem cell lines carrying mutations in <i>TARDBP</i> encoding TDP-43<sup>A382T</sup> and TDP-43<sup>G348C</sup>, two common yet understudied ALS TDP-43 variants. Motor neurons (MNs) differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43<sup>A382T</sup> and TDP-43<sup>G348C</sup> MN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings suggest that MN dysfunction may precede the occurrence of TDP-43 pathology and neurodegeneration in ALS and further implicate synaptic and excitability defects in the pathobiology of this disease."],"journal":["iScience"],"pagination":["109166"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10905001"],"repository":["biostudies-literature"],"pubmed_title":["Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons."],"pmcid":["PMC10905001"],"pubmed_authors":["Franco-Flores AK","Lepine S","Haghi G","Abdian N","Castellanos-Montiel MJ","Maussion G","Nauleau-Javaudin A","Deneault E","Chen CX","Durcan TM","Chaineau M"],"additional_accession":[]},"is_claimable":false,"name":"Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons.","description":"Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in <i>TARDBP</i> (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR-Cas9, we engineered two homozygous knock-in induced pluripotent stem cell lines carrying mutations in <i>TARDBP</i> encoding TDP-43<sup>A382T</sup> and TDP-43<sup>G348C</sup>, two common yet understudied ALS TDP-43 variants. Motor neurons (MNs) differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43<sup>A382T</sup> and TDP-43<sup>G348C</sup> MN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings suggest that MN dysfunction may precede the occurrence of TDP-43 pathology and neurodegeneration in ALS and further implicate synaptic and excitability defects in the pathobiology of this disease.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-06-09T07:12:19.251Z","creation":"2025-04-07T04:46:31.865Z"},"accession":"S-EPMC10905001","cross_references":{"pubmed":["38433895"],"doi":["10.1016/j.isci.2024.109166"]}}