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Updated: Sep 6, 2025
Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans
Published on: September 7, 2021
Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration
Yuya Kishino1, Koji Matsukawa2, Taisei Matsumoto2
1Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
Abstract:
Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here, we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro using mass spectrometric analyses. We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. Taken together, our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies.
Insights
Casein kinase 1δ (CK1δ) phosphorylation of fused in sarcoma (FUS) protein increases FUS solubility and reduces neurotoxicity in ALS models. This suggests CK1δ/CK1ε-mediated phosphorylation is a potential therapeutic target for FUS proteinopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Aberrant cytoplasmic accumulation of fused in sarcoma (FUS) protein is a key feature in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.
- The role of FUS post-translational modifications, particularly phosphorylation, in its neurotoxicity remains incompletely understood.
Purpose of the Study:
- To investigate the impact of casein kinase 1δ (CK1δ) phosphorylation on FUS solubility and neurotoxicity.
- To explore the therapeutic potential of CK1δ/CK1ε-mediated phosphorylation in FUS proteinopathies.
Main Methods:
- In vitro mass spectrometric analysis to identify FUS phosphorylation sites by CK1δ.
- Cellular assays in human embryonic kidney 293 cells to assess FUS solubility after phosphorylation.
- Transgenic Drosophila models overexpressing FUS (wild-type and ALS-mutant) with coexpression of CK1δ or Dco to evaluate neuroprotective effects.
Main Results:
- CK1δ was identified to phosphorylate FUS at 10 serine/threonine residues in vitro.
- Phosphorylation by CK1δ or CK1ε significantly enhanced FUS solubility in HEK293 cells.
- Coexpression of CK1δ/Dco ameliorated FUS-induced retinal degeneration and extended lifespan in Drosophila models.
Conclusions:
- CK1δ/CK1ε-mediated phosphorylation represents a novel regulatory mechanism for FUS assembly and toxicity.
- Targeting CK1δ/CK1ε phosphorylation offers a potential therapeutic strategy for FUS proteinopathies like ALS.
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