Mutations: FUS Δ14
Modification: FUS: Virus
Disease Relevance: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: B6C3F1
Availability: Viral construct available through Thomas Kukar
This model uses adeno-associated virus (AAV) to introduce cDNA encoding mutant human FUS into the brains of wild-type mice. It is considered a model of the neuronal pathology observed in FUS proteinopathies, such as ALS and FTD (Verbeeck et al., 2012).
This model was created alongside two other AAV-mediated FUS models, one expressing wild-type human FUS and the other carrying the R521C mutation. Among these three models, FUSΔ14 mice had the most severe neuropathology when assessed three months after viral injection. Notably, FUSΔ14 mice exhibited significant mislocalization of FUS protein into the cytoplasm along with the formation of neuronal cytoplasmic inclusions (NCIs), reminiscent of those observed in a subset of ALS cases.
Transgene expression ramps up in the three weeks post-injection, and by three months of age the mice expressed transgenic FUS protein throughout the brain. The highest expression levels were observed in the cerebral cortex and hippocampus. Expression in the spinal cord is unknown. Compared to the other AAV models, FUSΔ14 mice showed the greatest cytoplasmic redistribution of FUS as well as the most inclusion pathology. FUS inclusions were present in about 20 percent of neurons in the cortex and hippocampus and often co-labeled with ubiquitin. TDP-43 pathology was not observed.
The mice appeared healthy when they were sacrificed at three months of age. They showed no obvious motor impairment, although it is unknown whether behavioral impairments would develop at more advanced ages. At three months of age, at least, neurodegeneration and reactive gliosis were not observed in the brain.
In this model, recombinant adeno-associated virus (AAV) is used to express mutant human FUS in the brain. The virus is injected into the ventricles of P0 pups. Expression of human FUS is driven by the cytomegalovirus enhancer/chicken β-actin promoter. The cDNA encodes C-terminal truncation, which lacks exon 14, and thus the entire nuclear localization signal. The AAV construct is AAV1-human p.G466VfsX14, as originally described in DeJesus-Hernandez et al., 2010.
AAV construct is available upon request from Thomas Kukar.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Motor Impairment
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- NMJ Abnormalities
- Muscle Atrophy
- Body Weight
- Premature Death
Cortical Neuron Loss
Lower Motor Neuron Loss
Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.
No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.
When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.
Research Models Citations
- Verbeeck C, Deng Q, Dejesus-Hernandez M, Taylor G, Ceballos-Diaz C, Kocerha J, Golde T, Das P, Rademakers R, Dickson DW, Kukar T. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener. 2012;7:53. PubMed.
- DeJesus-Hernandez M, Kocerha J, Finch N, Crook R, Baker M, Desaro P, Johnston A, Rutherford N, Wojtas A, Kennelly K, Wszolek ZK, Graff-Radford N, Boylan K, Rademakers R. De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis. Hum Mutat. 2010 May;31(5):E1377-89. PubMed.