title: Reduced sodium channel Na(v)1.1 levels in BACE1-null mice.
abstract: The Alzheimer BACE1 enzyme cleaves numerous substrates, with largely unknown physiological consequences. We have previously identified the contribution of elevated BACE1 activity to voltage-gated sodium channel Na(v)1.1 density and neuronal function. Here, we analyzed physiological changes in sodium channel metabolism in BACE1-null mice. Mechanistically, we first confirmed that endogenous BACE1 requires its substrate, the β-subunit Na(v)β(2), to regulate levels of the pore-forming α-subunit Na(v)1.1 in cultured primary neurons. Next, we analyzed sodium channel α-subunit levels in brains of BACE1-null mice at 1 and 3 months of age. At both ages, we found that Na(v)1.1 protein levels were significantly decreased in BACE1-null versus wild-type mouse brains, remaining unchanged in BACE1-heterozygous mouse brains. Interestingly, levels of Na(v)1.2 and Na(v)1.6 α-subunits also decreased in 1-month-old BACE1-null mice. In the hippocampus of BACE1-null mice, we found a robust 57% decrease of Na(v)1.1 levels. Next, we performed surface biotinylation studies in acutely dissociated hippocampal slices from BACE1-null mice. Hippocampal surface Na(v)1.1 levels were significantly decreased, but Na(v)1.2 surface levels were increased in BACE1-null mice perhaps as a compensatory mechanism for reduced surface Na(v)1.1. We also found that Na(v)β(2) processing and Na(v)1.1 mRNA levels were significantly decreased in brains of BACE1-null mice. This suggests a mechanism consistent with BACE1 activity regulating mRNA levels of the α-subunit Na(v)1.1 via cleavage of cell-surface Na(v)β(2). Together, our data show that endogenous BACE1 activity regulates total and surface levels of voltage-gated sodium channels in mouse brains. Both decreased Na(v)1.1 and elevated surface Na(v)1.2 may result in a seizure phenotype. Our data caution that therapeutic BACE1 activity inhibition in Alzheimer disease patients may affect Na(v)1 metabolism and alter neuronal membrane excitability in Alzheimer disease patients.
authors.affiliation: From the Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: From the Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and.
authors.forename: Manuel T
authors.initials: MT
authors.lastname: Gersbacher
authors.affiliation: the Department of Neurology, F. M. Kirby Neurobiology Center, Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Perrine
authors.initials: P
authors.lastname: Inquimbert
authors.affiliation: From the Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and. Electronic address: dora_kovacs@hms.harvard.edu.
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D012640:Seizures / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse