Polyglutamine-induced ion channels: A possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases

CAG repeats resulting in long polyglutamine tracts have been implicated in the pathogenesis of at least eight neurodegenerative diseases including Hun tington. Expression of polyglutamine repeats is required for disease and in creasing length of the repeats leads to earlier onset of illness (anticipat ion). Expression of polyglutamine repeats in cultured neurons leads to depo sition of intracellular aggregates resembling those found in amyloid diseas es, and to neurotoxicity. We report here that polyglutamine can induce larg e (19-220 pS), long-lived, (lifetime = 6 sec), non-selective (P-cation = P- anion) ion channels in planar phospholipid bilayer membranes, and that chan nel formation is enhanced by acidic pH. We propose that channel formation m ay be a mechanism of cellular toxicity in Huntington and other CAG repeat d isease. Published 2000 Wiley-Liss, Inc.(dagger)