Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD
<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...
| Váldodahkkit: | , , , , , , , , , |
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| Materiálatiipa: | Journal article |
| Giella: | English |
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Elsevier
2020
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| _version_ | 1826293185716944896 |
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| author | Dafinca, R Barbagallo, P Farrimond, L Candalija, A Scaber, J Ababneh, N Sathyaprakash, C Vowles, J Cowley, S Talbot, K |
| author_facet | Dafinca, R Barbagallo, P Farrimond, L Candalija, A Scaber, J Ababneh, N Sathyaprakash, C Vowles, J Cowley, S Talbot, K |
| author_sort | Dafinca, R |
| collection | OXFORD |
| description | <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> |
| first_indexed | 2024-03-07T03:26:13Z |
| format | Journal article |
| id | oxford-uuid:b91f7951-bcff-4eda-bc3b-4f4d82ea5263 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:26:13Z |
| publishDate | 2020 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:b91f7951-bcff-4eda-bc3b-4f4d82ea52632022-03-27T05:00:54ZImpairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTDJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b91f7951-bcff-4eda-bc3b-4f4d82ea5263EnglishSymplectic ElementsElsevier2020Dafinca, RBarbagallo, PFarrimond, LCandalija, AScaber, JAbabneh, NSathyaprakash, CVowles, JCowley, STalbot, K<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> |
| spellingShingle | Dafinca, R Barbagallo, P Farrimond, L Candalija, A Scaber, J Ababneh, N Sathyaprakash, C Vowles, J Cowley, S Talbot, K Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title | Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title_full | Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title_fullStr | Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title_full_unstemmed | Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title_short | Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD |
| title_sort | impairment of mitochondrial calcium buffering links mutations in c9orf72 and tardbp in ips derived motor neurons from patients with als ftd |
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