Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment
- Authors
- Park, Ju-Hwang; Jang, Hae Rim; Lee, In Young; Oh, Hye Kyung; Choi, Eui-Ju; Rhim, Hyangshuk; Kang, Seongman
- Issue Date
- 15-Sep-2017
- Publisher
- OXFORD UNIV PRESS
- Citation
- HUMAN MOLECULAR GENETICS, v.26, no.18, pp.3615 - 3629
- Indexed
- SCIE
SCOPUS
- Journal Title
- HUMAN MOLECULAR GENETICS
- Volume
- 26
- Number
- 18
- Start Page
- 3615
- End Page
- 3629
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/82232
- DOI
- 10.1093/hmg/ddx250
- ISSN
- 0964-6906
- 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 14-3-3 epsilon and 0 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.
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