Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS

Desiree M Baron, Tyler Matheny, Yen-Chen Lin, John D Leszyk, Kevin Kenna, Katherine V Gall, David P Santos, Maeve Tischbein, Salome Funes, Lawrence J Hayward, Evangelos Kiskinis, John E Landers, Roy Parker, Scott A Shaffer, Daryl A Bosco

Research output: Contribution to journalArticleAcademicpeer-review


Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. It is also unclear whether disease-linked proteins influence the proteome under conditions of translational repression. To address these questions, a quantitative proteomics approach was used to identify proteins that evade stress-induced translational repression in arsenite-treated cells expressing either wild-type or amyotrophic lateral sclerosis (ALS)-linked mutant FUS. This study revealed hundreds of proteins that are actively synthesized during stress-induced translational repression, irrespective of FUS genotype. In addition to proteins involved in RNA- and protein-processing, proteins associated with neurodegenerative diseases such as ALS were also actively synthesized during stress. Protein synthesis under stress was largely unperturbed by mutant FUS, although several proteins were found to be differentially expressed between mutant and control cells. One protein in particular, COPBI, was downregulated in mutant FUS-expressing cells under stress. COPBI is the beta subunit of the coat protein I (COPI), which is involved in Golgi to endoplasmic reticulum (ER) retrograde transport. Further investigation revealed reduced levels of other COPI subunit proteins and defects in COPBI-relatedprocesses in cells expressing mutant FUS. Even in the absence of stress, COPBI localization was altered in primary and human stem cell-derived neurons expressing ALS-linked FUS variants. Our results suggest that Golgi to ER retrograde transport may be important under conditions of stress and is perturbed upon the expression of disease-linked proteins such as FUS.

Original languageEnglish
Pages (from-to)2143-2160
Number of pages18
JournalHuman molecular genetics
Issue number13
Publication statusPublished - 1 Jul 2019
Externally publishedYes


  • Amyotrophic Lateral Sclerosis/genetics
  • Animals
  • Arsenites/pharmacology
  • Cell Line, Tumor
  • Coat Protein Complex I/metabolism
  • Cytoplasmic Granules/drug effects
  • Endoplasmic Reticulum/drug effects
  • Golgi Apparatus/drug effects
  • Humans
  • Mice
  • Motor Neurons/drug effects
  • Mutation
  • Protein Biosynthesis/drug effects
  • Proteomics
  • RNA-Binding Protein FUS/genetics


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