UMMS Affiliation

Department of Neurology

Publication Date

2020-10-21

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Molecular Biology | Nervous System Diseases | Neurology | Neuroscience and Neurobiology

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS.

Keywords

amyotrophic lateral sclerosis, ALS, mitochondria, protein phosphatase 1, dynamin-related protein 1

Rights and Permissions

Copyright © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41419-020-03102-8

Source

Choi SY, Lee JH, Chung AY, Jo Y, Shin JH, Park HC, Kim H, Lopez-Gonzalez R, Ryu JR, Sun W. Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis. Cell Death Dis. 2020 Oct 21;11(10):888. doi: 10.1038/s41419-020-03102-8. PMID: 33087694; PMCID: PMC7578657. Link to article on publisher's site

Journal/Book/Conference Title

Cell death and disease

Related Resources

Link to Article in PubMed

PubMed ID

33087694

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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