Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif
| Autor: | E. A. Kovrazhkina, R. K. Ovchinnikov, Vladimir L. Buchman, Tatyana A. Shelkovnikova, E. V. Bronovitsky, Michail S. Kukharsky, E. R. Sadchikova, T G Ermolkevich, I. L. Goldman, Natalia Ninkina, Hannah K. Robinson, A. A. Ustyugov, Sergey O. Bachurin, Alexey V. Deykin |
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| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Lethargy Cytoplasm Cytoplasmic inclusion Amino Acid Motifs RNA-binding protein Mice Transgenic Biology Article Mice Glial Fibrillary Acidic Protein Tremor Animals Sequence Deletion Inclusion Bodies Neurons RNA recognition motif Point mutation RNA Brain Phenotype Cell biology Mice Inbred C57BL Disease Models Animal Neurology Phosphopyruvate Hydratase Cancer research Disease Progression RNA-Binding Protein FUS Neurology (clinical) |
| Zdroj: | Amyotrophic lateral sclerosisfrontotemporal degeneration. 16(5-6) |
| ISSN: | 2167-9223 |
| Popis: | Mutations to the RNA binding protein, fused in sarcoma (FUS) occur in ∼5% of familial ALS and FUS-positive cytoplasmic inclusions are commonly observed in these patients. Altered RNA metabolism is increasingly implicated in ALS, yet it is not understood how the specificity with which FUS interacts with RNA in the cytoplasm can affect its aggregation in vivo. To further understand this, we expressed, in mice, a form of FUS (FUS ΔRRMcyt) that lacked the RNA recognition motif (RRM), thought to impart specificity to FUS-RNA interactions, and carried an ALS-associated point mutation, R522G, retaining the protein in the cytoplasm. Here we report the phenotype and results of histological assessment of the brain of transgenic mice expressing this isoform of FUS. Results demonstrated that neuronal expression of FUS ΔRRMcyt caused early lethality often preceded by severe tremor. Large FUS-positive cytoplasmic inclusions were found in many brain neurons; however, neither neuronal loss nor neuroinflammatory response was observed. In conclusion, the extensive FUS proteinopathy and severe phenotype of these mice suggests that affecting the interactions of FUS with RNA in vivo may augment its aggregation in the neuronal cytoplasm and the severity of disease processes. |
| Databáze: | OpenAIRE |
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