Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to
loss of motor function and early death. About 5% of cases are inherited, with
the majority of identified linkages in the gene encoding copper,
zinc-superoxide dismutase (SOD1). Strong evidence indicates that the SOD1
mutations confer dominant toxicity on the protein. To provide new insight into
mechanisms of ALS, we have generated and characterized a model for familial
ALS in Drosophila with transgenic expression of human SOD1.
Expression of wild type or disease-linked (A4V, G85R) mutants of human SOD1
selectively in motor neurons induced progressive climbing deficits. These
effects were accompanied by defective neural circuit electrophysiology, focal
accumulation of human SOD1 protein in motor neurons, and a stress response in
surrounding glia. However, toxicity was not associated with oligomerization of
SOD1 and did not lead to neuronal loss. These studies uncover cell-autonomous
injury by SOD1 to motor neurons in vivo, as well as non-autonomous
effects on glia, and provide the foundation for new insight into injury and
protection of motor neurons in ALS