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Biochim Biophys Acta. 2016 Oct;1862(10):2004-14. doi: 10.1016/j.bbadis.2016.07.015. Epub 2016 Jul 25.

Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS.

Author information

1
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA. Electronic address: meka229@g.uky.edu.
2
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA. Electronic address: jchen4@email.uky.edu.
3
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA. Electronic address: lisha.kuang@uky.edu.
4
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA. Electronic address: maar223@g.uky.edu.
5
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA. Electronic address: jianjunzhai@hotmail.com.
6
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Lexington VA Medical Center, Research & Development, Lexington, KY 40502, USA. Electronic address: haining@uky.edu.
7
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA. Electronic address: jgal2@uky.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Mutations in the Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) gene cause a subset of familial ALS cases and are also implicated in sporadic ALS. FUS is typically localized to the nucleus. The ALS-related FUS mutations cause cytoplasmic mis-localization and the formation of stress granule-like structures. Abnormal cytoplasmic FUS localization was also found in a subset of frontotemporal dementia (FTLD) cases without FUS mutations. To better understand the function of FUS, we performed wild-type and mutant FUS pull-downs followed by proteomic identification of the interacting proteins. The FUS interacting partners we identified are involved in multiple pathways, including chromosomal organization, transcription, RNA splicing, RNA transport, localized translation, and stress response. FUS interacted with hnRNPA1 and Matrin-3, RNA binding proteins whose mutations were also reported to cause familial ALS, suggesting that hnRNPA1 and Matrin-3 may play common pathogenic roles with FUS. The FUS interactions displayed varied RNA dependence. Numerous FUS interacting partners that we identified are components of exosomes. We found that FUS itself was present in exosomes, suggesting that the secretion of FUS might contribute to the cell-to-cell spreading of FUS pathology. FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. Our results provide insights into the physiological functions of FUS as well as important pathways where mutant FUS can interfere with cellular processes and potentially contribute to the pathogenesis of ALS.

KEYWORDS:

ALS; FUS; Neurodegeneration; Protein interaction network; Proteomics

PMID:
27460707
PMCID:
PMC5055831
DOI:
10.1016/j.bbadis.2016.07.015
[Indexed for MEDLINE]
Free PMC Article

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