mito-G93ASOD1 transgenic mice express mitochondrial inner membrane-tethered, human mutant SOD1G93A at high levels in brain, spinal cord, heart and skeletal muscle. Homozygous mito-G93ASOD1 mice exhibit progressive mitochondrial dysfunction and neurodegeneration, but no muscle denervation. These mice may be useful for studying the pathogenic role of SOD1 and mitochondria in familial amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).
Giovanni Manfredi, Weill Medical College of Cornell University
Genetic Background | Generation |
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Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
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.
The PrP-mitoSOD1G93A transgene (PrP-mito-G93ASOD1 or mito-G93ASOD1) was designed by Drs. Giovanni Manfredi and Jordi Magrane (Weill Medical College of Cornell University). The mito-G93ASOD1 fusion protein contains a mouse mitofilin (Immt) cDNA sequence encoding the first 187 amino acids (including the mitochondrial targeting presequence, MMP cleavage site and transmembrane domain) fused in-frame to the N-terminus of a human Cu,Zn superoxide dismutase cDNA sequence harboring the G93A mutation (SOD1G93A) associated with amyotrophic lateral sclerosis (ALS). The SOD1 start codon was removed and substituted with an in-frame 6 nt DNA linker. This mito-G93ASOD1 sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene at a unique XhoI site in the MoPrP.Xho plasmid vector.
In contrast to the publication, the donating investigator reports the resulting PrP-mito-G93ASOD1 transgene was microinjected into [C57BL/6J x CBA/J]F2 fertilized eggs. Male transgenic founders were bred with B6SJLF1/J female mice, and the founder line with the highest expression level (founder line 7) was characterized. At that time, quantitative real-time PCR determined hemizygotes had ~23 transgene copies (homozygotes had ~42 transgene copies), and breeding performance indicated autosomal integration of the transgenes. The mito-G93ASOD1 transgenic colony was maintained by breeding hemizygous males with B6SJLF1/J females for at least ten generations prior to sending males to The Jackson Laboratory Repository in 2014. Upon arrival, sperm was cryopreserved. To generate our live colony, an aliquot of the frozen sperm was used to fertilize oocytes from B6SJLF1/J mice (Stock No. 100012). Thereafter, the colony was maintained by breeding hemizygous mice with B6SJLF1/J mice every generation.
Expressed Gene | SOD1, superoxide dismutase 1, human |
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Expressed Gene | Immt, inner membrane protein, mitochondrial, mouse, laboratory |
Site of Expression |
Depending upon the experiment, the following may also be an appropriate control strain:
mito-WTSOD1 transgenic mice (Stock No. 024502).
Allele Name | transgene insertion 7, Giovanni Manfredi |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | mito-G93ASOD1; mito-SOD1G93A; Prp-mito-G93ASOD1 |
Gene Symbol and Name | Tg(Prnp-Immt/SOD1*G93A)7Gmnf, transgene insertion 7, Giovanni Manfredi |
Gene Synonym(s) | |
Promoter | Prnp, prion protein, mouse, laboratory |
Expressed Gene | SOD1, superoxide dismutase 1, human |
Expressed Gene | Immt, inner membrane protein, mitochondrial, mouse, laboratory |
Strain of Origin | (C57BL/6 x CBA)F1 |
Chromosome | UN |
Molecular Note | The mito-G93ASOD1 fusion protein contains a mouse mitofilin (Immt) cDNA sequence encoding the first 187 amino acids (including the mitochondrial targeting presequence, MMP cleavage site and transmembrane domain) fused in-frame to the N-terminus of a human Cu,Zn superoxide dismutase cDNA sequence harboring the G93A mutation (SOD1 |
When maintaining a live colony, hemizygous mice are bred to B6SJLF1/J mice (Stock No. 100012) every generation.
When using the mito-G93ASOD1 mouse strain in a publication, please cite the originating article(s) and include JAX stock #025403 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Hemiozygous or Non carrier for Tg(Prnp-Immt/SOD1*G93A)7Gmnf |
Frozen Mouse Embryo | B6SJL-Tg(Prnp-Immt/SOD1*G93A)7Gmnf/J Frozen Embryo | $2595.00 |
Frozen Mouse Embryo | B6SJL-Tg(Prnp-Immt/SOD1*G93A)7Gmnf/J Frozen Embryo | $2595.00 |
Frozen Mouse Embryo | B6SJL-Tg(Prnp-Immt/SOD1*G93A)7Gmnf/J Frozen Embryo | $3373.50 |
Frozen Mouse Embryo | B6SJL-Tg(Prnp-Immt/SOD1*G93A)7Gmnf/J Frozen Embryo | $3373.50 |
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