Mutations: FUS ΔNLS
Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: C57Bl/6J
Availability: Available through Daisuke Ito.
FUS (Fused in Sarcoma) is a member of a family of RNA-binding proteins with roles in transcription, RNA processing, RNA transport, and translation. Mutations in FUS, many of which are clustered near the nuclear localization signal (NLS) at the C-terminus, are linked to familial cases of ALS. Additionally, truncation and frameshift mutations can result in the deletion of the NLS.
A transgene containing myc-tagged human FUS lacking the NLS was expressed under control of the Thy1.2 promoter (Shiihashi et al., 2016). In the brain, the transgene was expressed at levels just below endogenous FUS (0.8x). At 24 weeks, transgene expression in the spinal cord was 50 percent lower than expression levels in the brain. In the spinal cord, human FUS was expressed highly in the pyramidal tract and to a lesser extent in spinal motor neurons.
Mice expressing ΔNLS-FUS began to exhibit motor abnormalities at 12 weeks of age with abnormal hind limb reflex and retraction. Progressive impairments in the hanging wire and accelerating Rotarod tests were observed by 20 weeks. Additionally, gait irregularities were observed at one year of age. By 60 weeks, transgenic mice exhibited an approximately 50 percent mortality rate. Motor imparement was similar in male and female animals.
In the motor cortex, ΔNLS-FUS was localized entirely in the cytoplasm while endogenous FUS was nuclear. By 24 weeks, cytoplasmic FUS aggregates positive for ubiquitin and p62 were observed in 74 percent of neurons. Ubiquitin-positive inclusions were not detected in anterior horn motor neurons by a year.
Increased microgliosis and astrocytosis were observed at one year in the motor cortex compared to non-transgenic controls. Additionally, ΔNLS-FUS mice had fewer neurons in the motor cortex at one year, but not at 15 weeks. No significant loss of spinal motor neurons was observed in the L5 anterior horn at a year.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Lower Motor Neuron Loss
- NMJ Abnormalities
- Muscle Atrophy
Cortical Neuron Loss
By 1 year, there was neuronal loss in the motor cortex.
Lower Motor Neuron Loss
Not observed at 1 year in the L5 anterior horn.
Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.
Microgliosis and astrocytosis were observed in the motor cortex.
Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.
Decreased by 48 weeks.
Approximately 50% mortality by 60 weeks of age.
Last Updated: 14 Apr 2017
Research Models Citations
- Shiihashi G, Ito D, Yagi T, Nihei Y, Ebine T, Suzuki N. Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. Brain. 2016 Sep;139(Pt 9):2380-94. Epub 2016 Jun 30 PubMed.
No Available Further Reading