Mutant SOD1 knockdown in all cell types ameliorates disease in G85R SOD1 mice with a limited additional effect over knockdown restricted to motor neurons.

Approximately 10% of patients with amyotrophic lateral sclerosis (ALS) have familial ALS (FALS), and 20% of FALS is caused by mutant Cu/Zn superoxide dismutase type 1 (MTSOD1). Previous studies have convincingly demonstrated that MTSOD1 expression in other cell types besides motor neurons (MNs) contributes to disease in MTSOD1 FALS transgenic mice. Using Cre/LoxP methods, we knocked down G85R SOD1 mRNA by 66% in all cell types in 3-month-old FALS transgenic mice, delaying disease onset and lengthening disease duration. Surprisingly, the effect on onset and early disease duration was similar to that seen in FALS transgenic mice with approximately 25% knockdown prenatally in G85R SOD1 mRNA restricted to MNs and some interneurons. These results demonstrate no clear cumulative effect on disease onset or early disease duration from knocking down G85R SOD1 in other cell types in addition to MNs/interneurons; the findings bring up the possibility that MTSOD1 has a pathogenic effect early in life that our later knockdown did not affect. Despite the more limited amelioration of disease than expected, the effect of the knockdown on disease supports the value of this approach in FALS patients and asymptomatic individuals with SOD1 mutations.