RRC ID 71987
Author Hata S, Fujishige S, Araki Y, Kato N, Araseki M, Nishimura M, Hartmann D, Saftig P, Fahrenholz F, Taniguchi M, Urakami K, Akatsu H, Martins RN, Yamamoto K, Maeda M, Yamamoto T, Nakaya T, Gandy S, Suzuki T.
Title Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction.
Journal J Biol Chem
Abstract Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.
Volume 284(52)
Pages 36024-36033
Published 2009-12-25
DOI 10.1074/jbc.M109.057497
PII S0021-9258(20)37413-5
PMID 19864413
PMC PMC2794718
MeSH ADAM Proteins / genetics ADAM Proteins / metabolism ADAM10 Protein ADAM17 Protein Alzheimer Disease / genetics Alzheimer Disease / metabolism* Amyloid Precursor Protein Secretases / genetics Amyloid Precursor Protein Secretases / metabolism* Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism* Animals Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism* Cell Line Humans Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Peptides / genetics Peptides / metabolism* Protease Nexins Receptors, Cell Surface / genetics Receptors, Cell Surface / metabolism*
IF 4.238
DNA material Alcadein a-FLAG /pcDNA3.1(+) (RDB19587) Alcadein b-FLAG /pcDNA3.1(+) (RDB19588) Alcadein g-FLAG /pcDNA3.1(+) (RDB19589)