The channel hypothesis of Huntington's disease

Extended tracts of polyglutamine (PG) have been implicated in the pathogeni city of the mutant protein huntingtin and have been shown to form ion chann els in planar lipid bilayers. These lines of evidence suggest that huntingt in and other PG mutant proteins may damage cells via a channel mechanism. T his mechanism could cause damage to the plasma membrane by running down ion ic gradients, discharging membrane potential; or allowing influx of toxic i ons such as Ca2+. PG damage to intracellular membranes such as the lysosoma l membrane or the mitochondrial membrane could also injure cells via leakag e of toxic enzymes or triggering of apoptosis. The channel mechanism is wel l-established for microbial toxins, and the existence of at least six other "amyloid" channels relevant to diseases such as Alzheimer's and Creutzfeld -Jakob, suggests that this may be a widespread pathogenic mechanism. (C) 20 01 Elsevier Science Inc.