Genes: FUS, TARDBP
Mutations: FUS ΔNLS
Modification: FUS: Transgenic; TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: C57Bl/6J
Availability: Available through Daisuke Ito.
This mouse model of ALS is a cross between the ΔNLS-FUS line, which overexpresses human FUS lacking the nuclear localization signal (NLS), and the TDP-43(WT) line, which overexpresses wild-type human TDP-43 (Shiihashi et al., 2016). Both lines utilize a Thy1 promoter. This double transgenic mouse line exhibited the similar, but more pronounced, phenotypes relative to the ΔNLS-FUS single transgenic line.
In the brain, the human FUS was expressed at levels just below endogenous FUS (0.7x). 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 and TDP-43 began to exhibit motor abnormalities at eight weeks of age with abnormal hind limb reflex and retraction. Progressive impairments in the hanging wire and accelerating Rotarod tests were observed by 12 weeks. Additionally, gait irregularities were observed at one year of age. By 60 weeks, transgenic mice exhibited a mortality rate of approximately 40 percent. Both male and female mice were included in these analyses.
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 79 percent of neurons. Ubiquitin-positive inclusions were not detected in anterior horn motor neurons by a year.
Increased microgliosis and astrocytosis were observed in the motor cortex compared to non-transgenic controls. Additionally, ΔNLS-FUS x TDP43 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 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.
Decreased by 48 weeks.
Approximately 40% 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