Mechanism of SOD1-linked ALS studied in C elegans and mouse models

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Neurodegeneration is a poorly understood biological phenomenon and an increasing public health challenge for our aging society. Discoveries of causal genetic mLitations have accelerated understanding the molecular mechanisms of these diseases. Mutations in Cu/Zn superoxide dismutase (SODI) have been linked to a subset of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease that leads to progressive paralysis. Understanding how a large number of S0D1 mutations, mostly single amino acid changes, cause the specific motor neuron degeneration may provide important insight into more prevalent sporadic ALS. To this end, we have developed novel SODI transgenic C. elegans and mice that exhibit neuronal dysfunction and locomotor defects. Protein;misfolding and aggregation, an increasingly common association with major neurodegenerative diseases, lare a main feature of both the invertebrate and the mammalian animal models. Initial characterization ofthe models traced the behavioral defects to synaptic dysfunctions. Here we propose to combine the use of the genetically tractable C. elegans and the mouse models to dissect the disease mechanism, including the role of protein aggregation. The elucidation may contribute to a better understanding of ALS as well as neurodegenerative diseases in general.