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

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.

Key words::

• Amyotrophic lateral sclerosis
• fused in sarcoma
• RNA recognition motif
• transgenic animals
• RNA binding

Declaration of interest: The authors declare no competing financial interests.

Acknowledgements

We are grateful to Don Cleveland for the kind gift of antibodies against both mouse FUS and human FUS. This work was supported by a Motor Neurone Disease Association Research Grant (Buchman/Apr13/6096) to VLB and Russian Scientific Fund No.14-14-01138 to NNN. Production of founders was partially supported by Transgenbank, IGB and the establishment of transgenic mouse colonies and phenotypical analysis – by Chernogolovka’s Resources Share Centre, State Contract 14.621.21.0008.

Supplementary material available online

Supplementary Figure 1 and 2, Video 1, to be found online at http://www.informahealthcare.com/doi/abs/10.3109/21678421.2015.1040994.