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.
We have examined the localization of contactin-associated protein (Caspr), the Shaker-type potassium channels, Kv1.1 and Kv1.2, their associated beta subunit, Kvbeta2, and Caspr2 in the myelinated fibers of the CNS. Caspr is localized to the paranodal axonal membrane, and Kv1.1, Kv1.2, Kvbeta2 and Caspr2 to the juxtaparanodal membrane. In addition to the paranodal staining, an internodal strand of Caspr staining apposes the inner mesaxon of the myelin sheath. Unlike myelinated axons in the peripheral nervous system, there was no internodal strand of Kv1.1, Kv1.2, Kvbeta2, or Caspr2. Thus, the organization of the nodal, paranodal, and juxtaparanodal axonal membrane is similar in the central and peripheral nervous systems, but the lack of Kv1.1/Kv1.2/Kvbeta2/Caspr2 internodal strands indicates that the oligodendrocyte myelin sheaths lack a trans molecular interaction with axons, an interaction that is present in Schwann cell myelin sheaths.
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