Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif

Robinson, Hannah, Deykin, Alexey V., Bronovitsky, Evgeny V., Ovchinnikov, Ruslan K., Ustyugov, Alexey A., Shelkovnikova, Tatyana ORCID: https://orcid.org/0000-0003-1367-5309, Kukharsky, Michail S., Ermolkevich, Tatyana G., Goldman, Igor L., Sadchikova, Elena R., Kovrazhkina, Elena A., Bachurin, Sergey O., Buchman, Vladimir L. ORCID: https://orcid.org/0000-0002-7631-8352 and Ninkina, Natalia ORCID: https://orcid.org/0000-0001-8570-5648 2015. Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 16 (5-6) , pp. 402-409. 10.3109/21678421.2015.1040994

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QR Microbiology
Uncontrolled Keywords:	Amyotrophic lateral sclerosis, fused in sarcoma, RNA recognition motif, transgenic animals, RNA binding
Publisher:	Taylor & Francis
ISSN:	2167-8421
Date of Acceptance:	8 March 2015
Last Modified:	17 Nov 2022 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/83517

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