Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/7/1246 |
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| author | René Günther Arun Pal Chloe Williams Vitaly L. Zimyanin Maria Liehr Cläre von Neubeck Mechthild Krause Mrudula G. Parab Susanne Petri Norman Kalmbach Stefan L. Marklund Jared Sterneckert Peter Munch Andersen Florian Wegner Jonathan D. Gilthorpe Andreas Hermann |
| author_facet | René Günther Arun Pal Chloe Williams Vitaly L. Zimyanin Maria Liehr Cläre von Neubeck Mechthild Krause Mrudula G. Parab Susanne Petri Norman Kalmbach Stefan L. Marklund Jared Sterneckert Peter Munch Andersen Florian Wegner Jonathan D. Gilthorpe Andreas Hermann |
| author_sort | René Günther |
| collection | DOAJ |
| description | Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated <i>SOD1</i> mutations (D90A<sup>hom</sup>, R115G<sup>het</sup> or A4V<sup>het</sup>) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90A<sup>hom</sup> MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115G<sup>het</sup> and A4V<sup>het</sup> mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS. |
| first_indexed | 2024-03-09T11:59:48Z |
| format | Article |
| id | doaj.art-a384eecc4dc6440ea19379b4d2551e7d |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T11:59:48Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a384eecc4dc6440ea19379b4d2551e7d2023-11-30T23:05:32ZengMDPI AGCells2073-44092022-04-01117124610.3390/cells11071246Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALSRené Günther0Arun Pal1Chloe Williams2Vitaly L. Zimyanin3Maria Liehr4Cläre von Neubeck5Mechthild Krause6Mrudula G. Parab7Susanne Petri8Norman Kalmbach9Stefan L. Marklund10Jared Sterneckert11Peter Munch Andersen12Florian Wegner13Jonathan D. Gilthorpe14Andreas Hermann15Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Neurology, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Integrative Medical Biology, Umeå University, 90187 Umeå, SwedenDepartment of Neurology, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Neurology, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyGerman Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, GermanyGerman Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, GermanyDepartment of Neurology, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Medical Biosciences, Clinical Chemistry, Umeå University, 90187 Umeå, SwedenCenter for Regenerative Therapies Dresden, Technical University Dresden, 01307 Dresden, GermanyDepartment of Clinical Sciences, Umeå University, 90187 Umeå, SwedenDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Integrative Medical Biology, Umeå University, 90187 Umeå, SwedenTranslational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, GermanyLittle is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated <i>SOD1</i> mutations (D90A<sup>hom</sup>, R115G<sup>het</sup> or A4V<sup>het</sup>) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90A<sup>hom</sup> MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115G<sup>het</sup> and A4V<sup>het</sup> mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.https://www.mdpi.com/2073-4409/11/7/1246<i>SOD1</i>ALS1mitochondrialive cell imagingaxonal trafficking |
| spellingShingle | René Günther Arun Pal Chloe Williams Vitaly L. Zimyanin Maria Liehr Cläre von Neubeck Mechthild Krause Mrudula G. Parab Susanne Petri Norman Kalmbach Stefan L. Marklund Jared Sterneckert Peter Munch Andersen Florian Wegner Jonathan D. Gilthorpe Andreas Hermann Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS Cells <i>SOD1</i> ALS1 mitochondria live cell imaging axonal trafficking |
| title | Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS |
| title_full | Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS |
| title_fullStr | Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS |
| title_full_unstemmed | Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS |
| title_short | Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS |
| title_sort | alteration of mitochondrial integrity as upstream event in the pathophysiology of sod1 als |
| topic | <i>SOD1</i> ALS1 mitochondria live cell imaging axonal trafficking |
| url | https://www.mdpi.com/2073-4409/11/7/1246 |
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