Experimental Genetics as a Tool for Understanding Pathogenesis of ALS

Abstract

The identification of genes linked to a variety of neurodegenerative diseases allows the examination of the pathogenic mechanisms underlying these illnesses. The use of transgenic and gene-targeted mice approaches has allowed investigators to perturb the normal pattern of gene expression in mammals and to determine the phenotypic consequences of expressing wild-type/mutant genes linked to neurodegenerative diseases. Over the past decade, transgenic mice strategies have allowed researchers to reproduce features of human neurodegenerative disease in mice, and among the various models, the mutant superoxide dismutase-1 (SOD-1) mice—a model of familial amyotrophic lateral sclerosis (FALS)—has become a prototype for investigations of mechanisms of selective neuronal degeneration. In this chapter, we will discuss briefly the clinical, genetic, and neuropathological features of ALS, and illustrate how transgenic approaches are valuable tools for testing the role of copper in the pathogenesis of SOD-1-linked ALS. The delivery of copper to SOD-1 in yeast is mediated through a soluble protein called CCS (copper chaperone for SOD-1) and by generating CCS-deficient mice, we document that CCS is necessary to selectively deliver copper to SOD-1 to activate this mammalian metalloenzyme. These CCS knockout mice are valuable, in crossbreeding studies using mutant SOD-1 mice, to test directly whether copper in mutant SOD-1 is critical to cause motor-neuron degeneration in SOD-1-linked FALS. Finally, we will review the lessons we have learned from the SOD-1 transgenic mice models regarding the pathogenic mechanisms of FALS.