Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice.
Sodium channel beta4 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 beta4 as an expressed sequence tag (EST) that was significantly down-regulated in the striatum of HD model mice and patients. Reduction in beta4 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 beta4 expression even at the symptomatic stage. Overexpression of beta4 induced neurite outgrowth in Neuro2a cells, and caused a thickening of dendrites and increased density of dendritic spines in hippocampal primary neurons, indicating that beta4 modulates neurite outgrowth activities. These results suggest that down-regulation of beta4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and patients with HD.
Oyama
Fumitaka
F
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan.
Miyazaki
Haruko
H
Sakamoto
Naoaki
N
Becquet
Celine
C
Machida
Yoko
Y
Kaneko
Kumi
K
Uchikawa
Chiharu
C
Suzuki
Taishi
T
Kurosawa
Masaru
M
Ikeda
Tetsurou
T
Tamaoka
Akira
A
Sakurai
Takashi
T
Nukina
Nobuyuki
N
D000818:Animals; D015152:Blotting, Northern; D001923:Brain Chemistry / Q000235:genetics; D019295:Computational Biology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D016208:Databases, Factual; D015536:Down-Regulation / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology*; D016501:Neurites / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000096:biosynthesis*; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
C497241:Scn4b protein, mouse; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D004247:DNA