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Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment
- Source :
- Human Molecular Genetics. 26:3615-3629
- Publication Year :
- 2017
- Publisher :
- Oxford University Press (OUP), 2017.
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss in the spinal cord and brain. Mutations in the superoxide dismutase 1 (SOD1) gene have been linked to familial ALS. To elucidate the role of SOD1 mutations in ALS, we investigated 14-3-3, a crucial regulator of cell death that was identified in patients with familial ALS. In a transgenic mouse model (SOD1-G93A) of ALS, 14-3-3 co-localized with mutant SOD1 aggregates and was more insoluble in the spinal cords of mutant SOD1 transgenic mice than in those of wild-type mice. Immunofluorescence and co-immunoprecipitation experiments showed that the 14-3-3ɛ and θ isoforms interact with mutant SOD1 aggregates in the juxtanuclear quality control compartment of N2a neuroblastoma cells. Fluorescence loss in photobleaching experiments revealed that movement of the isoforms of 14-3-3 was markedly reduced in SOD1 aggregates. Bax translocation into and cytochrome c release from the mitochondria were promoted by the sequestration of 14-3-3 into mutant SOD1 aggregates, increasing cell death. Mutant SOD1 aggregates were dissolved by the Hsp104 chaperone, which increased the interaction of 14-3-3 with Bax, reducing cell death. Our study demonstrates that mutant SOD1 inhibits 14-3-3-mediated cell survival. This information may contribute to the identification of a novel therapeutic target for ALS.
- Subjects :
- Male
0301 basic medicine
Genetically modified mouse
Programmed cell death
Cell Survival
animal diseases
Transgene
Mutant
SOD1
Mice, Transgenic
Mitochondrion
Superoxide dismutase
Mice
03 medical and health sciences
Genetics
medicine
Animals
Humans
Immunoprecipitation
Amyotrophic lateral sclerosis
Molecular Biology
Genetics (clinical)
Motor Neurons
Cell Death
biology
Superoxide Dismutase
Amyotrophic Lateral Sclerosis
nutritional and metabolic diseases
General Medicine
medicine.disease
nervous system diseases
Cell biology
Disease Models, Animal
030104 developmental biology
14-3-3 Proteins
Spinal Cord
nervous system
Biochemistry
Mutation
biology.protein
Female
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....1a6d3a6cd179a50bb9b81bcd392fdc11