mito-G93ASOD1 transgenic mice have the mouse prion protein promoter directing expression of mutant human SOD1G93A with N-terminal fusion of the mouse mitofilin mitochondrial targeting signal, MMP cleavage site and transmembrane domain. This results in expression of SOD1G93A that is anchored to the outer side of the mitochondrial inner membrane (i.e., facing the intermembrane space) at high levels in brain, spinal cord, heart and skeletal muscle. High expression is observed in both neurons and astrocytes. Low to undetectable levels of protein are reported in kidney, lung, spleen and liver. The mito-G93ASOD1 protein in high expressing tissues oligomerizes and acquires enzymatic activity. Hemizygous mito-G93ASOD1 mice are viable and fertile with central nervous system mitochondria defects but no overt neuromuscular abnormalities. Homozygous mito-G93ASOD1 mice exhibit mitochondrial dysfunction and neurodegeneration that results in morbidity/death by one year. Specifically, homozygotes develop a progressive disease characterized by body weight loss (by 8 months in females), muscle weakness (by 8 months in both sexes), brain atrophy (by 8 months in males), and motor impairment (by 3 months in females; by 6 months in males). The phenotype is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling (by 12 months of age). Importantly, homozygous mito-G93ASOD1 mice show no evidence of muscle denervation (a major pathological feature of ALS).
Of note, homozygous mito-G93ASOD1 accumulate mitochondrial SOD1G93A at levels comparable to those found in the high-expressor hemizygous B6SJL-Tg-(SOD1*G93A)1Gur/J mice (Stock No. 002726).
The mito-WTSOD1 transgenic mice (Stock No. 024502) are a control strain for mito-G93ASOD1 mice.
