Inducible Site-specific Expression of Mutant SOD1

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MN). Approximately 10% of ALS cases are familial (known as FALS), and approximately 25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). There is convincing evidence that mutant (MT) SOD kills MN because of toxicity rather than a deficiency in dismutase activity. However, the basis for this toxicity remains unclear as does effective treatment for this devastating fatal disease. Surprisingly, although mice that carry MTSOD with its endogenous promoter as a transgene develop MN disease (MND), a restricted expression of MTSOD in neurons or astrocytes fails to induce MND. In this proposal, we hypothesize that MTSOD requires expression early in embryonic life in MN in order to cause an ALS phenotype. In order to test this hypothesis, we will generate a transgenic mouse that selectively expresses MTSOD in MN (and some interneurons) starting early in embryonic life. The MTSOD expression will be inducible so that we will also be able to determine how early expression must occur and how long this expression has to last in order to kill MN. In addition, these mice will also express a luciferase reporter gene in MN, so that the mice can provide a source for dissociated spinal cord cell cultures with tagged MN for use in screens for effective drugs in ALS.