1.D.9 Polyglutamine Ion Channel (PG-IC) Family
Several human progressive neurodegenerative diseases, called "CAG repeat diseases" and including Huntington&146;s disease and several spinocerebellar atoxias, are caused by expanded CAG triplet repeats that code for polyglutamine tracts of variable lengths. Increasing the lengths of these tracts contributes to early onset of these illnesses. The mutant protein, Huntingtin, forms insoluble aggregates resembling β -sheet amyloid fibriles.
Polyglutamine (average Molecular Weight of 6000) has been shown to induce large, long lived, non-selective (Pcation= Panion), voltage-dependent ion channels in planar phospholipid bilayer membranes. Channel formation is enhanced by acidic pH, suggesting that acidic endosomal/lysosomal compartments might be targets of polyglutamine. Glutamine itself, and both polyglutamate and polyasparagine are inactive in inducing channel-formation in lipid bilayers. Polyglutamine channels might promote leakage leading to metabolic stress, disruption of homeostatic mechanisms and neurotoxicity. Channel formation may therefore be relevant to the pathological conditions accompanying disease.