Huntington's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Huntington's Disease, including details on genetics, causes, symptoms, treatment.

Neuronal vulnerability in mouse models of Huntington's disease: membrane channel protein changes.

Ariano MA, Wagle N, Grissell AE

Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064-3095, USA. marjorie.ariano@rosalindfranklin.edu

Huntington's disease (HD) is caused by a polyglutamine expansion that results in atrophy of the striatum and frontal cortex during disease progression. HD-susceptible striatal neurons are affected chronologically with initial degeneration of the striatopallidal neurons then the striatonigral projections, whereas large aspiny striatal interneurons (LAN) survive. Two classes of critical membrane proteins were evaluated in transgenic mouse models to determine their association with HD susceptibility, which leads to dysfunction and death in selected striatal neuron populations. We examined potassium (K+) channel protein subunits that form membrane ionophores conducting inwardly and outwardly rectifying K+ currents. K+ channel protein staining was diminished substantially in the HD striatal projection neurons but was not expressed in the HD-resistant LAN. Because loss of K+ channel subunits depolarizes neurons, other voltage-gated ionophores will be affected. N-methyl-D-aspartate (NMDA) receptors and their phosphorylation by cyclic AMP were studied as a mechanism contributing to excitotoxic vulnerability in striatal projection neurons that would lose voltage regulation after diminished K+ channels. NR1 subunits showed significant elevation in the HD transgenic projection systems but were expressed at very low levels in LAN. NR1 subunit phosphorylation by cyclic AMP also was enhanced in striatal projection neurons but not in LAN. Cyclic AMP-driven phosphorylation of NMDA receptors increases the channel open time and elevates neuronal glutamate responsiveness, which may lead to excitotoxicity. Together our data suggest that changes in these proteins and their modification may predispose striatal projection neurons to dysfunction and then degeneratation in HD and provide a mechanism for LAN resistance in the disease.

Published 25 May 2005 in J Neurosci Res, 80(5): 634-45.
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