Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS
Article first published online: 8 DEC 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 69, Issue 1, pages 152–162, January 2011
How to Cite
Ito, D., Seki, M., Tsunoda, Y., Uchiyama, H. and Suzuki, N. (2011), Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol., 69: 152–162. doi: 10.1002/ana.22246
- Issue published online: 28 JAN 2011
- Article first published online: 8 DEC 2010
- Manuscript Accepted: 27 AUG 2010
- Manuscript Revised: 24 JUL 2010
- Manuscript Received: 18 MAY 2010
- Eisai Co. Ltd.
- Ministry of Education, Culture, Sports, Science, and Technology of Japan. Grant Number: 18590955
The fused in sarcoma/translated in liposarcoma (FUS/TLS) protein was recently identified as a cause of familial amyotrophic lateral sclerosis (ALS), as well as a major component of the inclusion bodies found in subtypes of frontotemporal lobar degeneration (FTLD). These diseases now are collectively known as the novel clinical spectrum, FUS proteinopathy. ALS-linked mutations of FUS are clustered in the C-terminal region; however, the molecular properties of mutant FUS remain unclear. To gain insight into the pathogenesis of FUS proteinopathy, we examined the biochemical and cellular characteristics of mutant FUS in expressing cells.
Methods and Results:
Expression of ALS-linked FUS mutations resulted in their assembly into cytoplasmic stress granules (SGs), cellular structures that package mRNA and RNA-binding proteins during cell stress. A deletion mutant series revealed that the C-terminal region in FUS is critical for nuclear retention via Ran guanosine triphosphatase-dependent transport machinery. A parallel study of subcellular distribution revealed that ALS-linked mutants additively disturb the function of the C-terminus for nuclear traffic, resulting in cytoplasmic accumulation and the formation of SGs.
This study demonstrates that mutant FUS, which is missing the nuclear traffic activity of the C-terminus, is dislocated to cytoplasm and assembled into SGs, indicating that disruption of translational regulation and metabolism of mRNA via inappropriate/excessive SGs may be crucial for FUS proteinopathies. Our findings provide new biological and pathological insights into the FUS protein that should help our understanding of the pathogenesis of ALS/FTLD. Ann Neurol 2010