title: Growth arrest-specific 1 binds to and controls the maturation and processing of the amyloid-beta precursor protein.
abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by cerebral deposition of amyloid-β (Aβ), a series of peptides derived from the processing of the amyloid-β precursor protein (APP). To identify new candidate genes for AD, we recently performed a transcriptome analysis to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions. This strategy identified CALHM1 (calcium homeostasis modulator 1), a gene modulating AD age at onset and Aβ metabolism. Here, we focused our attention on another candidate identified using this screen, growth arrest-specific 1 (Gas1), a gene involved in the central nervous system development. We found that Gas1 formed a complex with APP and controlled APP maturation and processing. Gas1 expression inhibited APP full glycosylation and routing to the cell surface by leading to a trafficking blockade of APP between the endoplasmic reticulum and the Golgi. Gas1 expression also resulted in a robust inhibition of APP transport into multivesicular bodies, further demonstrating that Gas1 negatively regulated APP intracellular trafficking. Consequently, Gas1 overexpression led to a reduction in Aβ production, and conversely, Gas1 silencing in cells expressing endogenously Gas1 increased Aβ levels. These results suggest that Gas1 is a novel APP-interacting protein involved in the control of APP maturation and processing.
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Chapuis
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D023061:Gene Order; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D016564:Amyloid beta-Protein Precursor; D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins