Mutations: SOD1 G37R
Modification: SOD1: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: C57BL/6J x C3H/HeJ)F2
This early transgenic mouse model of ALS overexpresses mutant human SOD1 (Wong et al., 1995). The transgene is regulated by the endogenous human SOD1 promoter and regulatory elements, driving expression in the brain and spinal cord. Symptoms of motor neuron disease appear around four to six months of age. The mice lose weight and develop motor impairments including reduced stride length, decreased spontaneous movement, tremors, limb weakness, poor grooming, and muscle wasting. Ultimately the mice become paralyzed and die at about seven months of age.
This entry describes SOD1 (G37R) line 29 mice on a hybrid background. Of the original SOD1 (G37R) lines, line 29 is particularly well-characterized and was later developed into a congenic line at The Jackson Lab (see below). Line 29 mice express mutant human SOD1 at levels four- to fivefold higher than endogenous murine SOD1 in the CNS. Dismutase activity in the spinal cord was increased about sevenfold compared with enzymatic activity in non-Tg mice.
Line 29 mice develop motor deficits around four to six months of age, including reduced spontaneous movement and reduced stride length. When lifted by their tails, they have difficulty extending their hindlimbs. They develop tremors, limb weakness, poor grooming, and muscle atrophy.
Neuropathologically, these mice develop robust pathology in the spinal cord, including loss of motor neurons. Astrogliois in the spinal cord occurs early, by 11 weeks of age, and becomes more severe over time. Vacuoles appear within motor neurons and associated neuropils around 19 weeks of age. By this time, motor neuron loss is underway. The loss of motor neurons is accompanied by denervation of muscles, SOD1 accumulation in axons, and extensive muscle atrophy.
Loss of upper motor neurons is not a feature of this model, although brainstem neurons develop vacuoles. Cytoplasmic vacuoles were bounded by a single membrane and frequently contained degenerating mitochondria.
Hemizygous mice survive about six to eight months.
The transgene is a 12kb DNA fragment encoding human SOD1 with the G37R mutation. The human SOD1 promoter drives transgene expression.
SOD1 (G37R) (congenic) - This congenic line is derived from line 29 and backcrossed to C57BL/6J. It is available through The Jackson Lab, Stock# 008229. Some reports indicate that mice on a C57BL/6-congenic background survive about one year (e.g., Ezzi et al. 2010); however, according to The Jackson Lab website, mice in their colony survive up to 500 days.
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
- Cytoplasmic Inclusions
Cortical Neuron Loss
Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.
Lower Motor Neuron Loss
Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.
Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.
Denervated endplates have been observed.
Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.
Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.
Loss of body weight is observed.
Mice survive about 6 to 8 months.
- Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995 Jun;14(6):1105-16. PubMed.
- Ezzi SA, Larivière R, Urushitani M, Julien JP. Neuronal over-expression of chromogranin A accelerates disease onset in a mouse model of ALS. J Neurochem. 2010 Dec;115(5):1102-11. PubMed.
- Wang J, Xu G, Gonzales V, Coonfield M, Fromholt D, Copeland NG, Jenkins NA, Borchelt DR. Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis. 2002 Jul;10(2):128-38. PubMed.