A MUTATED ACETYLCHOLINE-RECEPTOR SUBUNIT CAUSES NEURONAL DEGENERATIONIN C-ELEGANS

Neurotoxicity through abnormal activation of membrane channels is a po tential cause of neurodegenerative disease. Here we show that a gain-o f-function mutation, deg 3(u662), leads to the degeneration of a small set of neurons in the nematode C. elegans. The deg-3 gene encodes a n icotinic acetylcholine receptor alpha subunit, which in the region of transmembrane domain II is most similar to the neuronal alpha 7 subuni ts from rat and chicken. The u662 mutation changes a residue in the se cond transmembrane domain, the domain thought to form the channel pore . A similar change in the equivalent amino acid in the chick protein p roduces channels that desensitize slowly. Channel hyperactivity may un derlie the degenerations seen in the C. elegans deg-3(u662) mutants, s ince antagonists of nicotinic acetylcholine receptors suppress the deg -3(u662) mutant phenotypes.