The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
| Autor: | Thomas Brännström, Matthis Synofzik, Elin Forsgren, Jonathan D. Gilthorpe, Ulrika Nordström, Per Zetterström, Isil Keskin, Stefan L. Marklund, Manuela Lehmann, Dale J. Lange, Peter M. Andersen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal diseases Mutant Protein aggregation 0302 clinical medicine Superoxide Dismutase-1 metabolism [Oxygen] Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis Motor Neurons metabolism [Superoxide Dismutase-1] biology Chemistry Biochemistry and Molecular Biology genetics [Superoxide Dismutase-1] Cell biology Oxygen tension medicine.anatomical_structure pathology [Fibroblasts] metabolism [Fibroblasts] Astrocyte pathology [Motor Neurons] SOD1 genetics [Mutation] Patient-derived cells Pathology and Forensic Medicine Superoxide dismutase 03 medical and health sciences Cellular and Molecular Neuroscience medicine Humans ddc:610 pathology [Amyotrophic Lateral Sclerosis] Original Paper Disulfide bond metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis Wild type Neurotoxicity nutritional and metabolic diseases Fibroblasts medicine.disease nervous system diseases Oxygen Cytosol 030104 developmental biology Cell culture Mutation biology.protein Superoxide dismutase 1 (SOD1) Neurology (clinical) Protein disorder Biokemi och molekylärbiologi 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Acta neuropathologica 138(1), 85-101 (2019). doi:10.1007/s00401-019-01986-1 |
| ISSN: | 1432-0533 |
| Popis: | 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 O2 is required for formation of the bond, we reasoned that low O2 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 O2 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 O2 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. Electronic supplementary material The online version of this article (10.1007/s00401-019-01986-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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