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-? (A?), a series of peptides derived from the processing of the amyloid-? 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 A? 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 A? production, and conversely, Gas1 silencing in cells expressing endogenously Gas1 increased A? levels. These results suggest that Gas1 is a novel APP-interacting protein involved in the control of APP maturation and processing.

SUBMITTER: Chapuis J 

PROVIDER: S-EPMC3279048 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature