Pathological roles of sodium channel β4 subunit in Huntington disease transgenic mice

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Sodium channelβ4 (β4) is a very recently identified auxiliary subunit of the voltage gated-sodium channels Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, psychiatric disturbances and dementia. HD is caused by a polyglutamine (polyQ) expansion in the amino terminus of huntingtin, a 350 kDa cytoplasmic protein. To find primarily affected gene in HD pathogenesis, we profiled HD transgenic mice using a high-density oligonucleotide array and identified P4 as an EST that was significantly downregulated in the striatum of HD model mice and patients. Reduction ofβ4 started at a presymptomatic stage of the HD model mice, whereas other voltage-gated ion channels subunits were decreased later. In contrast, spinal cord neurons, which generate only negligible levels of expanded polyglutamine aggregates, maintained normal levels of β4 expression even at the symptomatic stage. Overexpression of β4 in Neuro2a cells promoted neurite extension and increased the number of F-actin rich filopodia-like protrusions, indicating that 134 modulates neurite outgrowth activities. Recently we identified β4 as a new substrate for β-site APP cleaving enzyme (BACE1), a membrane-bound aspartyl protease that cleaves amyloid precursor protein (APP). While coexpression of BACE1 together with β4 further accelerated neurite extension, the number of filopodia-like protrusions was reduced. Furthermore, overexpression of β4 in hippocampal primary neurons caused a thickening of dendrites and increased density of dendritic spines in the neurons. These results suggest that downregulation in β4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and HD patients.