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

Marisa Kamelgarn, Jing Chen, Lisha Kuang, Alexandra Arenas, Jianjun Zhai, Haining Zhu, Jozsef Gal

Research output: Contribution to journalArticlepeer-review

78 Citations (SciVal)


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.

Original languageEnglish
Pages (from-to)2004-2014
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number10
StatePublished - Oct 1 2016

Bibliographical note

Funding Information:
We thank Dr. Jose Abisambra (Sanders-Brown Center on Aging, University of Kentucky) for his help with the establishment of the primary cortical neuron cultures. This study was in part supported by the National Institutes of Neurological Disorder and Stroke grant R01NS077284 , ALS Association grant 6SE340 and VA MERIT award I01 BX002149 (to HZ) as well as a Research Support Grant from the University of Kentucky Office of the Vice President for Research (to JG). MK is supported by the National Institute of Environmental Health Sciences training grant T32 ES007266 .

Publisher Copyright:
© 2016 Elsevier B.V.


  • ALS
  • FUS
  • Neurodegeneration
  • Protein interaction network
  • Proteomics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


Dive into the research topics of 'Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS'. Together they form a unique fingerprint.

Cite this