PMID- 30863976 OWN - NLM STAT- MEDLINE DCOM- 20200721 LR - 20200721 IS - 1432-0533 (Electronic) IS - 0001-6322 (Print) IS - 0001-6322 (Linking) VI - 138 IP - 1 DP - 2019 Jul TI - The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension. PG - 85-101 LID - 10.1007/s00401-019-01986-1 [doi] AB - Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O(2) is required for formation of the bond, we reasoned that low O(2) tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low O(2) tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O(2) tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression. FAU - Keskin, Isil AU - Keskin I AD - Department of Medical Biosciences, Pathology, Umea University, 90185, Umea, Sweden. FAU - Forsgren, Elin AU - Forsgren E AD - Department of Pharmacology and Clinical Neuroscience, Umea University, 90187, Umea, Sweden. FAU - Lehmann, Manuela AU - Lehmann M AD - Department of Pharmacology and Clinical Neuroscience, Umea University, 90187, Umea, Sweden. FAU - Andersen, Peter M AU - Andersen PM AD - Department of Pharmacology and Clinical Neuroscience, Umea University, 90187, Umea, Sweden. FAU - Brannstrom, Thomas AU - Brannstrom T AD - Department of Medical Biosciences, Pathology, Umea University, 90185, Umea, Sweden. FAU - Lange, Dale J AU - Lange DJ AD - Department of Neurology, Hospital for Special Surgery and Weill Cornell Medical Center, New York, NY, 10021, USA. FAU - Synofzik, Matthis AU - Synofzik M AD - Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany. AD - German Research Center for Neurodegenerative Diseases (DZNE), 72076, Tubingen, Germany. FAU - Nordstrom, Ulrika AU - Nordstrom U AD - Department of Pharmacology and Clinical Neuroscience, Umea University, 90187, Umea, Sweden. FAU - Zetterstrom, Per AU - Zetterstrom P AD - Department of Medical Biosciences, Clinical Chemistry, Umea University, 90185, Umea, Sweden. FAU - Marklund, Stefan L AU - Marklund SL AD - Department of Medical Biosciences, Clinical Chemistry, Umea University, 90185, Umea, Sweden. stefan.marklund@umu.se. FAU - Gilthorpe, Jonathan D AU - Gilthorpe JD AUID- ORCID: 0000-0002-6884-4774 AD - Department of Pharmacology and Clinical Neuroscience, Umea University, 90187, Umea, Sweden. jonathan.gilthorpe@umu.se. LA - eng GR - 2012.0091/Knut och Alice Wallenbergs Stiftelse/International GR - 2015-02804/Vetenskapsradet/International GR - NA/Bertil Hallstens Forskningsstiftelse/International GR - NA/Torsten Soderbergs Stiftelse/International GR - FO2015-0234/Hjarnfonden/International GR - NA/Ulla-Carin Lindquist Stiftelse (SE)/International GR - NA/Neuroforbundet/International GR - NA/Stratneuro (SE)/International GR - NA/Vasterbotten Lans Landsting/International GR - NA/Kempestiftelserna/International GR - NA/Else Kroner-Fresenius-Stiftung/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190312 PL - Germany TA - Acta Neuropathol JT - Acta neuropathologica JID - 0412041 RN - EC 1.15.1.1 (Superoxide Dismutase-1) RN - S88TT14065 (Oxygen) SB - IM MH - Amyotrophic Lateral Sclerosis/metabolism/*pathology MH - Fibroblasts/metabolism/*pathology MH - Humans MH - Motor Neurons/*pathology MH - Mutation/genetics MH - Oxygen/*metabolism MH - Superoxide Dismutase-1/genetics/metabolism PMC - PMC6570705 OTO - NOTNLM OT - Amyotrophic lateral sclerosis (ALS) OT - Disulfide bond OT - Oxygen tension OT - Patient-derived cells OT - Protein aggregation OT - Protein disorder OT - Superoxide dismutase 1 (SOD1) COIS- The authors declare that they have no conflict of interest. EDAT- 2019/03/14 06:00 MHDA- 2020/07/22 06:00 PMCR- 2019/03/12 CRDT- 2019/03/14 06:00 PHST- 2018/10/12 00:00 [received] PHST- 2019/03/01 00:00 [accepted] PHST- 2019/02/25 00:00 [revised] PHST- 2019/03/14 06:00 [pubmed] PHST- 2020/07/22 06:00 [medline] PHST- 2019/03/14 06:00 [entrez] PHST- 2019/03/12 00:00 [pmc-release] AID - 10.1007/s00401-019-01986-1 [pii] AID - 1986 [pii] AID - 10.1007/s00401-019-01986-1 [doi] PST - ppublish SO - Acta Neuropathol. 2019 Jul;138(1):85-101. doi: 10.1007/s00401-019-01986-1. Epub 2019 Mar 12.