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Table 3 Rodent models of ALS-FUS

From: Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

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. -
  1. 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
  2. AAV Adeno-associated virus, WT Wild-type, SC Spinal cord, FUS Fused-in-sarcoma, MAPT Microtubule-associated protein tau
  3. aModel publicly available through Jackson Laboratories as of June 2016