Elucidation of molecular mechanisms of amyotrophic lateral sclerosis

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This research was aimed to elucidate molecular mechanisms of neurodegeneration in amyotrophic lateral sclerosis (ALS), and, furthermore, to develop therapeutic strategies for ALS. The project focused on 1. detailed mutational analysis of Cu/Zn SOD gene in familial ALS, 2. analysis of conformational changes of mutant Cu/Zn SOD proteins, and 3. creation of transgenic mice for familial ALS. Among 33 families with familial ALS, we have identified 7 mutations in the SOD1 gene including 3 novel ones (Ala4Thr, Cys111Tyr and Glu133Stop). By transient expression of mutant Cu/Zn SOD proteins in COS cells, we have found that the mutant Cu/Zn SOD proteins possesses properties for aggregate formation and altered mobility on SDS-PAGE analysis, supporting that the mutant proteins have conformations changes. We have established transgenic mouse lines carrying Ala4Thr and Ile113Thr, of which Ile113Thr mice have developed muscular weakness in the hindlegs. Based on the accomplishments obtained through this project, molecular mechanisms of neurodegeneration caused by mutant Cu/Zn SOD proteins will further be investigated.