Y. Hirakura et al., Polyglutamine-induced ion channels: A possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases, J NEUROSC R, 60(4), 2000, pp. 490-494
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)