Research Models

PrP-hFUS (R495X)

Synonyms: PrP-hFUS*R495X transgenic line PX78, PrP-hFUS(R495X) line PX78

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Species: Mouse
Genes: FUS
Mutations: FUS R495X
Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6.Cg-Tg(Prnp-FUS*R495X)78Ljh/J
Genetic Background: Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic.
Availability: Congenic available through The Jackson Lab: Stock# 019728; Cryopreserved

Summary

These transgenic mice overexpress mutant human FUS within the nervous system via the mouse prion protein promoter (Prp). The transgene encodes a truncated form of human FUS, which lacks the nuclear localization sequence, resulting in cytoplasmic accumulation of the protein. This model was initially generated on a mixed background, but a congenic is now available through JAX. To date, only characterization of the mixed background model has been reported (Tibshirani et al., 2015).

On a mixed background, hemizygous mice carry 11 to 15 copies of the FUS transgene and exhibit about fourfold protein overexpression in the brain and spinal cord compared with endogenous FUS levels. Both hemizygous and homozygous mice are viable and fertile.

Although hemizygous mice displayed no overt signs of motor weakness, muscular abnormalities were detected in the hindlimbs by electromyography (EMG). These abnormalities were detectable by eight to 12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

Hemizygous mice exhibit cytoplasmic mislocalization of human FUS consistent with the lack of a nuclear localization sequence. Robust cytoplasmic accumulation of human FUS protein was reported in cortical neurons, deep cerebellar nuclei, lumbar spinal cord anterior horn cells, and hippocampal neurons. Importantly, some residual nuclear FUS staining remained. Despite the high levels of cytoplasmic FUS, inclusions were absent and there was no evidence of neuronal loss.

According to the JAX website, hemizygous mice on a mixed background occasionally develop intestinal swelling and paralytic ileus leading to premature death (50 percent of the original cohort died around 118 days of age). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

Modification Details

These mice express a mutant form of human FUS carrying a truncation mutation near the C-terminus. The transgene is driven by the mouse prion protein (Prp) promoter. The mutation abrogates the nuclear localization sequence and leads to cytoplasmic mislocalization of FUS.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Motor Impairment
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions

No Data

  • Muscle Atrophy
  • Body Weight
  • Gliosis

Cortical Neuron Loss

Not observed.

Lower Motor Neuron Loss

Not observed.

Cytoplasmic Inclusions

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

Gliosis

No data.

NMJ Abnormalities

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

Muscle Atrophy

No data.

Motor Impairment

Not observed.

Body Weight

No data.

Premature Death

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

Last Updated: 06 Mar 2018

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References

Paper Citations

  1. Tibshirani M, Tradewell ML, Mattina KR, Minotti S, Yang W, Zhou H, Strong MJ, Hayward LJ, Durham HD. Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet. 2015 Feb 1;24(3):773-86. Epub 2014 Sep 30 PubMed.

External Citations

  1. The Jackson Lab: Stock# 019728

Further Reading

No Available Further Reading