Sodium channel β4 subunit:: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice

Sodium channel beta 4 is a very recently identified auxiliary subunit of the voltage-gated sodium channels. To find the primarily affected gene in Huntington's disease (HD) pathogenesis, we profiled HD transgenic mice using a high-density oligonucleotide array and identified beta 4 as an expressed sequence tag (EST) that was significantly down-regulated in the striatum of HD model mice and patients. Reduction in beta 4 started at a presymptomatic stage in HD mice, whereas other voltage-gated ion channel subunits were decreased later. In contrast, spinal cord neurons, which generate only negligible levels of expanded polyglutamine aggregates, maintained normal levels of beta 4 expression even at the symptomatic stage. Overexpression of beta 4 induced neurite outgrowth in Neuro2a cells, and caused a thickening of dendrites and increased density of dendritic spines in hippocampal primary neurons, indicating that beta 4 modulates neurite outgrowth activities. These results suggest that down-regulation of beta 4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and patients with HD.