Title
Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS
UMMS Affiliation
Department of Neurology; Mass Spectrometry Facility; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Publication Date
2019-07-01
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry | Genetics and Genomics | Nervous System Diseases | Neurology | Neuroscience and Neurobiology
Abstract
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.
Keywords
stress response, arsenites, cop i, golgi apparatus, neurodegenerative disorders, neurons, repression, stress, protein biosynthesis, proteomics, granules
DOI of Published Version
10.1093/hmg/ddz048
Source
Baron DM, Matheny T, Lin YC, Leszyk JD, Kenna K, Gall KV, Santos DP, Tischbein M, Funes S, Hayward LJ, Kiskinis E, Landers JE, Parker R, Shaffer SA, Bosco DA. Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS. Hum Mol Genet. 2019 Jul 1;28(13):2143-2160. doi: 10.1093/hmg/ddz048. PMID: 30806671; PMCID: PMC6586143. Link to article on publisher's site
Journal/Book/Conference Title
Human molecular genetics
Related Resources
PubMed ID
30806671
Repository Citation
Baron D, Matheny T, Lin Y, Leszyk JD, Kenna KP, Gall KV, Santos DP, Tischbein M, Funes S, Hayward LJ, Kiskinis E, Landers JE, Parker R, Shaffer SA, Bosco D. (2019). Quantitative proteomics identifies proteins that resist translational repression and become dysregulated in ALS-FUS. Neurology Publications. https://doi.org/10.1093/hmg/ddz048. Retrieved from https://escholarship.umassmed.edu/neuro_pp/456