Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity
| Autor: | Makiko Nakagawa, Keiko Nakayama, Yujiao Yu, Noriko Ishida, Akane Morohoshi, Naoki Suzuki, Tadashi Nakagawa, Masashi Aoki |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cytoplasm Biology medicine.disease_cause Mice 03 medical and health sciences Transactivation 0302 clinical medicine Ubiquitin Valosin Containing Protein Cyclins Genetics medicine Animals Molecular Biology Gene Genetics (clinical) Cyclin Adenosine Triphosphatases Mutation SKP Cullin F-Box Protein Ligases Amyotrophic Lateral Sclerosis Ubiquitination General Medicine Transfection Cell biology 030104 developmental biology Ubiquitin ligase complex biology.protein 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Human Molecular Genetics. 28:3486-3497 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddz119 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by a progressive decline in motor function. Genetic analyses have identified several genes mutated in ALS patients, and one of them is Cyclin F gene (CCNF), the product of which (Cyclin F) serves as the substrate-binding module of a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex. However, the role of Cyclin F in ALS pathogenesis has remained unclear. Here, we show that Cyclin F binds to valosin-containing protein (VCP), which is also reported to be mutated in ALS, and that the two proteins colocalize in the nucleus. VCP was found to bind to the NH2-terminal region of Cyclin F and was not ubiquitylated by SCFCyclin F in transfected cells. Instead, the ATPase activity of VCP was enhanced by Cyclin F in vitro. Furthermore, whereas ALS-associated mutations of CCNF did not affect the stability of Cyclin F or disrupt formation of the SCFCyclin F complex, amino acid substitutions in the VCP binding region increased the binding ability of Cyclin F to VCP and activity of VCP as well as mislocalization of the protein in the cytoplasm. We also provided evidence that the ATPase activity of VCP promotes cytoplasmic aggregation of transactivation responsive region (TAR) DNA-binding protein 43, which is commonly observed in degenerating neurons in ALS patients. Given that mutations of VCP identified in ALS patients also increase its ATPase activity, our results suggest that Cyclin F mutations may contribute to ALS pathogenesis by increasing the ATPase activity of VCP in the cytoplasm, which in turn increases TDP-43 aggregates. |
| Databáze: | OpenAIRE |
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