| Sumari: | <div>TDP-43 dysfunction is common to 97% of amyotrophic lateral sclerosis (ALS) cases, including those with mutations in <em>C9orf72</em>. To investigate how <em>C9ORF72</em> mutations drive cellular pathology in ALS and to identify convergent mechanisms between <em>C9ORF72</em> and <em>TARDBP</em> mutations, we analyzed motor neurons (MNs) derived from induced pluripotent stem cells (iPSCs) from patients with ALS. <em>C9ORF72</em> iPSC-MNs have higher Ca<sup>2+</sup> release after depolarization, delayed recovery to baseline after glutamate stimulation, and lower levels of calbindin compared with CRISPR/Cas9 genome-edited controls. <em>TARDBP</em> iPS-derived MNs show high glutamate-induced Ca<sup>2+</sup> release. We identify here, by RNA sequencing, that both <em>C9ORF72</em> and <em>TARDBP</em> iPSC-MNs have upregulation of Ca<sup>2+</sup>-permeable AMPA and NMDA subunits and impairment of mitochondrial Ca<sup>2+</sup> buffering due to an imbalance of MICU1 and MICU2 on the mitochondrial Ca<sup>2+</sup> uniporter, indicating that impaired mitochondrial Ca<sup>2+</sup> uptake contributes to glutamate excitotoxicity and is a shared feature of MNs with <em>C9ORF72</em> or <em>TARDBP</em> mutations.</div>
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