Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis
Abstract Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial d...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708166 |
| _version_ | 1797284684152963072 |
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| author | Amit U Joshi Nay L Saw Hannes Vogel Anna D Cunnigham Mehrdad Shamloo Daria Mochly‐Rosen |
| author_facet | Amit U Joshi Nay L Saw Hannes Vogel Anna D Cunnigham Mehrdad Shamloo Daria Mochly‐Rosen |
| author_sort | Amit U Joshi |
| collection | DOAJ |
| description | Abstract Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient‐derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients. |
| first_indexed | 2024-03-07T17:52:17Z |
| format | Article |
| id | doaj.art-ea660dbc23c84d028c105fb382682139 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:52:17Z |
| publishDate | 2018-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-ea660dbc23c84d028c105fb3826821392024-03-02T13:58:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-03-01103n/an/a10.15252/emmm.201708166Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosisAmit U Joshi0Nay L Saw1Hannes Vogel2Anna D Cunnigham3Mehrdad Shamloo4Daria Mochly‐Rosen5Department of Chemical and Systems Biology Stanford University School of Medicine Stanford CA USABehavioral and Functional Neuroscience Laboratory Department of Neurosurgery Stanford University School of Medicine Stanford CA USADepartment of Pathology Stanford University School of Medicine Stanford CA USADepartment of Chemical and Systems Biology Stanford University School of Medicine Stanford CA USABehavioral and Functional Neuroscience Laboratory Department of Neurosurgery Stanford University School of Medicine Stanford CA USADepartment of Chemical and Systems Biology Stanford University School of Medicine Stanford CA USAAbstract Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient‐derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.https://doi.org/10.15252/emmm.201708166amyotrophic lateral sclerosisdynamin‐related protein 1fission 1mitochondrial dysfunctionProtein–Protein interactions |
| spellingShingle | Amit U Joshi Nay L Saw Hannes Vogel Anna D Cunnigham Mehrdad Shamloo Daria Mochly‐Rosen Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis EMBO Molecular Medicine amyotrophic lateral sclerosis dynamin‐related protein 1 fission 1 mitochondrial dysfunction Protein–Protein interactions |
| title | Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis |
| title_full | Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis |
| title_fullStr | Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis |
| title_full_unstemmed | Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis |
| title_short | Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis |
| title_sort | inhibition of drp1 fis1 interaction slows progression of amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis dynamin‐related protein 1 fission 1 mitochondrial dysfunction Protein–Protein interactions |
| url | https://doi.org/10.15252/emmm.201708166 |
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