PUBLICATION
Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis
- Authors
- Choi, S.Y., Lee, J.H., Chung, A.Y., Jo, Y., Shin, J.H., Park, H.C., Kim, H., Lopez-Gonzalez, R., Ryu, J.R., Sun, W.
- ID
- ZDB-PUB-201023-3
- Date
- 2020
- Source
- Cell Death & Disease 11: 888 (Journal)
- Registered Authors
- Chung, Ah-Young, Park, Hae-Chul
- Keywords
- none
- MeSH Terms
-
- Mice, Inbred C57BL
- Induced Pluripotent Stem Cells/drug effects
- Induced Pluripotent Stem Cells/metabolism*
- Neurodegenerative Diseases/genetics
- Neurodegenerative Diseases/metabolism
- Protein Phosphatase 1/metabolism*
- Mice, Transgenic
- Mitochondria/metabolism*
- Amyotrophic Lateral Sclerosis/genetics*
- Amyotrophic Lateral Sclerosis/metabolism*
- Animals
- Cell Death/genetics
- Cell Death/physiology
- Disease Models, Animal
- Mitochondrial Proteins/metabolism
- Motor Neurons/drug effects
- Motor Neurons/metabolism
- Zebrafish
- Mutation/genetics
- PubMed
- 33087694 Full text @ Cell Death Dis.
Citation
Choi, S.Y., Lee, J.H., Chung, A.Y., Jo, Y., Shin, J.H., Park, H.C., Kim, H., Lopez-Gonzalez, R., Ryu, J.R., Sun, W. (2020) Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis. Cell Death & Disease. 11:888.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping