Table 3.
Rodent models of ALS-FUS
| Study | Species | Model type | Background | Phenotype | Neuropathology | Gene expression analysis | Other |
|---|---|---|---|---|---|---|---|
| Kino et al. [37] | Mouse | Transgenic knockout (FUS -/-) | Mixed C57BL/6-ICR | Hyperactivity, reduction in anxiety, lowered body weight. No reduction in motor activity or observation of ALS phenotypic features. | Non-progressive vacuolation of CA3 region at 8-10 weeks. No evidence of neurodegeneration | No significant enrichment of specific profiles or changes in expression of other ALS-FTD related genes | Underexpression of FUS mRNA |
| Robinson et al. [67] | Mouse | Transgenic, FUS gene including R522G mutation and lacking RNA recognition motif | B6CBAF1/J | Lowered body weight, early lethality, pronounced tremor around two days before death | Large cytoplasmic FUS-positive inclusions in cortex and brainstem. No evidence of neurodegeneration | Not studied. | Significant FUS overexpression |
| Shelkovnikova et al. [73] | Mouse | Transgenic, using human aggregate prone FUS-variant lacking Nuclear localization signal and RNA binding motif (expressed at lower levels than endogenous FUS) | Mixed C57BL/6-CBA | Severe motor dysfunction at ~3 months, death within 2 weeks of symptom onset | FUS-positive inclusions in lower motor-neuron cell bodies, some ubiquinated inclusions. Significant SC neuronal loss and neuroinflammation. Prominent muscular atrophy | Not studied. | - |
| Verbeeck et al. [92] | Mouse | Somatic brain transgenic using intracerebral injection of AAV incorporating either R521C, ΔR14, or WT-overexpression | B6C3F1 | Healthy at time of death (3 months), no obvious motor impairment in any line | Increased cytoplasmic FUS expression in both mutants, however only some ΔR14 animals showed actual FUS-positive, ubiquinated inclusions. No evidence of neurodegeneration | Not studied. | High levels of FUS mutants within cytoplasm |
| Mitchell et al. [47]a | Mouse | Transgenic, over-expressing human WT FUS (hFUS +/+) | C57BL/6 | Rapid decline in motor function from 4 weeks old, hind limb paralysis at 8 weeks | Intense perinuclear and cytoplasmic FUS staining in cortical neurons without neuronal loss. Granular cytoplasmic FUS inclusions in spinal cord with neuronal loss and astrogliosis | Not studied. | Increased nuclear and cytosolic FUS levels |
| Qiu et al. [61]a | Mouse | Transgenic expressing mutant R521C construct | C57BL/6 | Severe motor dysfunction – spastic paraplegia, muscle wasting, abnormal gait etc. Death within 6 weeks of symptom onset | Significant (~50 %) loss of motor neurons with moderate astrogliosis in the spinal cord. FUS expression mainly seen in nuclei. Dendritic and synaptic defects in both SC and cortical neurons | R521C mutation causes splicing defects in genes that regulate synaptic functions. 766 genes involved in range of cellular functions identified that are differentially expressed between mutant and WT mice | FUS-R521C–associated DNA damage causes changes in downstream bdnf signalling |
| Sephton et al. [70]a | Mouse | Transgenic, Cre-recombinase approach. Created two lines expressing either R521G mutation or overexpressing WT FUS at low levels | C57BL/6 | Both lines showed severe motor dysfunction followed by early lethality. FUSR521G mice that escaped early lethality showed less pronounced motor dysfunction and deficits in spatial awareness | No FUS proteinopathy or aggregation in either line. No evidence of neuronal loss. Denervation of neuromuscular junctions and muscular atrophy in both lines | Pre-symptomatic FUSWT – differential expression of 185 genes, particularly related to DNA repair and regulation of cell proliferation. No statistically significant expression changes in FUSR521G mice | Reduced levels of R521C mRNA at synapses in response to mGluR activation. |
| Sharma et al. [71] | Mouse | Transgenic, Cre-LoxP with expression of WT human FUS, R521C or P525L mutation at MAPT locus | C57BL/6 | Both mutant lines showed hind limb weakness (P525L more severe) with no effect on survival. No phenotype in WT line | Progressive, mutation-dependent neurodegeneration and denervation of NMJ. Large increase in cytoplasmic FUS aggregation without inclusion formation. Additional astrocytosis and microgliosis in mutant SC but not WT | Not studied. | Additional KO model demonstrates loss of FUS alone not responsible for motor phenotype |
| Scekic‐Zahirovic et al. [69] | Mouse | Transgenic, knock-in mice using ablation of NLS (exon 15), and knock-out (-/-) mice lines | C57BL/6 | Immediate perinatal lethality of both lines from respiratory insufficiency | Cytoplasmic FUS mislocalization in transgenic line without inclusion or stress-granule formation. Knock-in line showed reduced motor neuron numbers associated with neuronal apoptosis. FUS mislocalization affected HDAC1 aggregation | 353 genes differentially expressed by both lines in the same direction compared to wild-type. Both lines showed significant splicing alterations | Cross with specific Cre-line rescued FUS mislocalization but not perinatal lethality phenotype. |
| Huang et al. [30, 29] | Rat | Transgenic expressing mutant FUS R521C construct. Additional model overexpressing human WT FUS | Sprague Dawley | Progressive paralysis of both fore and hind limbs in R521C mutant model but not in human WT overexpressing model. Spatial awareness and memory deficits in mutant line | Ubiquitinated, diffuse cytoplasmic FUS expression and glial activation in mutant FUS model but not WT model. Hippocampal and cortical neuron loss in both models | Not studied. | - |
Despite several models utilising the same R521C mutation and transgenic approach, results notably vary. Two knock-out models created before the identification of the significance of FUS in ALS are not included for clarity
AAV Adeno-associated virus, WT Wild-type, SC Spinal cord, FUS Fused-in-sarcoma, MAPT Microtubule-associated protein tau
aModel publicly available through Jackson Laboratories as of June 2016