Modeling Lou Gehrig's disease in the fruit fly

摘要

FALS is a complex disorder and its pathogenesis has yet to be clearly determined. Investigations in model organisms, like those reported in this issue of the Proceedings (1), will provide critical information for dissection of the structure-function and genotype-phenotype relations for FALS. As noted by Phillips et al. (1), model organisms may be particularly enlightening in defining the molecular abnormalities among patients with FALS who do not have mutations in SOD1. For those with SOD1 mutations, there is a growing body of evidence that the pathogenesis of their motor neuron degeneration does not represent simply the inhibition of dismutase activity with the degree of involvement proportional to the residual catalytic activity. Other possibilities include, for example, that FALS may result from alterations of SOD1 functions that have yet to be determined or that interference with the dismutation of superoxide is a proximate but not immediate cause of the neuronal loss. Since SOD1 is a ho-modimer and FALS is an autosomal dominant disorder, it remains likely that a dominant negative effect of the SOD1 mutations on a critical function of this protein in motor neurons will play a role in the etiology of FALS. An accurate and detailed understanding of the pathogenesis of FALS is important in developing appropriate therapies (6, 21, 22), and studies in model organisms are making valuable contributions.