beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase.
Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and gamma-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. Much has been discovered on the properties of these proteases; however, regulatory mechanisms of enzyme-substrate interaction in neurons and their involvement in pathological changes are still not fully understood. It is mainly because of the membrane-associated cleavage of these proteases and the lack of information on new substrates processed in a similar way to APP. Here, using RNA interference-mediated BACE1 knockdown, mouse embryonic fibroblasts that are deficient in either BACE1 or presenilins, and BACE1-deficient mouse brain, we show clear evidence that beta subunits of voltage-gated sodium channels are sequentially processed by BACE1 and gamma-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.
Pubmed ID: 15824102 RIS Download
Alzheimer Disease | Amino Acid Sequence | Amyloid Precursor Protein Secretases | Amyloid beta-Protein Precursor | Animals | Aspartic Acid Endopeptidases | Binding Sites | Blotting, Western | Brain | Cell Line | Cell Membrane | Cells, Cultured | Detergents | Endopeptidases | Fibroblasts | Genetic Vectors | Humans | Mice | Mice, Inbred C57BL | Mice, Knockout | Microscopy, Fluorescence | Molecular Sequence Data | Neurons | Phosphoric Monoester Hydrolases | Protein Binding | Protein Structure, Tertiary | RNA Interference | Sequence Homology, Amino Acid | Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization | Transfection