Modification: SOD1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: Transgene injected into hybrid (C57BL/6J x C3H/HeJ)F2 embryos.
Availability: Unknown status of the hybrid line. A congenic line is available through The Jackson Lab: Stock# 008248; Cryopreserved
This transgenic mouse was one of the first ALS models on the scene and has remained in use for decades due to its severe lower motor neuron degeneration and progressive motor impairment. The SOD1-G85R model was originally generated on a mixed genetic background (Bruijn et al., 1997). It was subsequently backcrossed to B6 to generate a congenic line, currently distributed through the Jackson Lab. This entry describes the initial characterization of this model on a mixed genetic background.
In these mice the endogenous human SOD1 promoter drives expression of mutant SOD1. In the CNS, expression levels are initially quite low, less than endogenous levels, but they double by end stage. The mutant SOD1 enzyme does not have dismutase activity, and SOD1 activity in spinal cord extracts is comparable to that seen in non-Tg mice.
Hemizygous SOD1-G85R mice appear normal through early adulthood. Symptoms appear around eight months of age, generally starting with reduced grip strength in one hindlimb. The disease then progresses rapidly. Within days the affected hindlimb becomes paralyzed, affecting posture and impairing locomotion. The weakness/paralysis then spreads to the other hindlimb and then to the forelimbs. Paralysis sets in within two weeks of symptom onset.
The motor decline and paralysis exhibited by these mice is paralleled by selective degeneration of lower motor neurons. Axon loss is not present prior to the first clinical signs, at which time about 25 percent of large motor axons are missing and another 10 percent are actively degenerating. By end stage, two weeks later, about 66 percent of the large axons are gone and half the remaining axons are degenerating. Smaller-caliber axons (<5 μm in diameter) were not affected. By end stage, some motor neurons in the ventral horn were also lost.
In addition to neuronal degeneration, these mice develop abundant glial pathology in the spinal cord. Astrogliosis and microgliosis are detected by 6. 5 months of age and become more severe at end stage. Notably, astrocytes contained inclusions of SOD1, which appeared by six months of age and became more abundant as the disease progressed. In addition, levels of the glial glutamate transporter (GLT-1) decreased, leading to glutamate-mediated excitotoxicity.
A small number of motor neurons also displayed diffuse aggregates that were immunoreactive for SOD1 and ubiquitin. These aggregates appeared before onset of clinical symptoms and became larger and more numerous as the disease progressed.
Deficits in the axonal transport of mitochondria have been reported, but appear to be secondary to axonal degeneration, because they are measurable only at end stage after axonal degeneration is well underway (Marinkovic et al., 2012).
SOD1-G85R (congenic) - A congenic line (B6.Cg-Tg(SOD1*G85R)148Dwc/J) is available through The Jackson Lab, Stock# 008248; Cryopreserved. According to the JAX website, congenic mice have a longer lifespan (median 361 days). After the onset of motor impairment, the disease progresses rapidly, with death at 12 to 13 months of age.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cortical Neuron Loss
Cortical Neuron Loss
Lower Motor Neuron Loss
Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.
Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.
Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.
Denervation of muscle fibers is observed.
Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.
Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.
Hemizygous mice start to lose weight at about 9 months of age.
End stage is characterized by paralysis at about 10 months of age.
- Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997 Feb;18(2):327-38. PubMed.
- Marinkovic P, Reuter MS, Brill MS, Godinho L, Kerschensteiner M, Misgeld T. Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4296-301. PubMed.
- Wang J, Farr GW, Zeiss CJ, Rodriguez-Gil DJ, Wilson JH, Furtak K, Rutkowski DT, Kaufman RJ, Ruse CI, Yates JR, Perrin S, Feany MB, Horwich AL. Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1392-7. PubMed.
- Farr GW, Ying Z, Fenton WA, Horwich AL. Hydrogen-deuterium exchange in vivo to measure turnover of an ALS-associated mutant SOD1 protein in spinal cord of mice. Protein Sci. 2011 Oct;20(10):1692-6. PubMed.
- Vande Velde C, McDonald KK, Boukhedimi Y, McAlonis-Downes M, Lobsiger CS, Bel Hadj S, Zandona A, Julien JP, Shah SB, Cleveland DW. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One. 2011;6(7):e22031. PubMed.