2. Academic Validation
  3. Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration

Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration

  • J Biol Chem. 2022 Aug;298(8):102191. doi: 10.1016/j.jbc.2022.102191.
Yuya Kishino 1,  Koji Matsukawa 2,  Taisei Matsumoto 2,  Ryota Miyazaki 3,  Tomoko Wakabayashi 4,  Takashi Nonaka 5,  Fuyuki Kametani 5,  Masato Hasegawa 5,  Tadafumi Hashimoto 6,  Takeshi Iwatsubo 7
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 3 Department of Neuropathology, 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.
  • 4 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Innovative Dementia Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 5 Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
  • 6 Department of Neuropathology, 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; Department of Innovative Dementia Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: [email protected].
  • 7 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: [email protected].
PMID: 35753345 DOI: 10.1016/j.jbc.2022.102191
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.

Keywords

ALS; CK1δ/ε; Drosophila; frontotemporal lobar degeneration; fused in sarcoma; neurodegeneration; phosphorylation.

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