Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment

TLDR

Mutations in the Cu/Zn superoxide dismutase gene (SOD1) are found in ~15% of familial ALS patients, and transgenic animals expressing mutant SOD1 in all tissues develop an ALS‑like phenotype. The study aimed to determine whether neuron‑specific expression of mutant SOD1 is sufficient to produce an ALS‑like phenotype. Transgenic mice carrying the G37R mutation driven by the neurofilament light chain promoter were generated to express mutant SOD1 selectively in neurons. These mice expressed high levels of human SOD1 in neuronal tissues, especially large motor neurons, yet displayed no motor deficits up to 1.5 years, suggesting neuron‑specific mutant SOD1 alone is insufficient to cause disease in mice.

Abstract

Mutations were identified in the Cu/Zn superoxide dismutase gene (SOD1) in ∼15% of patients with familial amyotrophic lateral sclerosis. Transgenic animals expressing mutant SOD1 in all tissues develop an ALS-like phenotype. To determine whether neuron-specific expression of mutant SOD1 is sufficient to produce such a phenotype, we generated transgenic animals carrying the G37R mutation that is associated with the familial form of ALS (FALS), which is driven by the neurofilament light chain promoter. The transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the large motor neurons of the spinal cord, but they show no apparent motor deficit at up to 1.5 years of age. Our animal model suggests that neuron-specific expression of ALS-associated mutant human SOD1 may not be sufficient for the development of the disease in mice.