The channel hypothesis of Huntington's disease.
Extended tracts of polyglutamine (PG) have been implicated in the pathogenicity of the mutant protein huntingtin and have been shown to form ion channels in planar lipid bilayers. These lines of evidence suggest that huntingtin and other PG mutant proteins may damage cells via a channel mechanism. This mechanism could cause damage to the plasma membrane by running down ionic gradients, discharging membrane potential; or allowing influx of toxic ions such as Ca(2+). PG damage to intracellular membranes such as the lysosomal membrane or the mitochondrial membrane could also injure cells via leakage of toxic enzymes or triggering of apoptosis. The channel mechanism is well-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.
Kagan
B L
BL
Department of Psychiatry, Neuropsychiatric Institute and Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90024-1759, USA. bkagan@mednet.ucla.edu
Hirakura
Y
Y
Azimov
R
R
Azimova
R
R
D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D018911:Trinucleotide Repeats
C086055:HTT protein, human; D000071058:Huntingtin Protein; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine