Helen & Robert Appel Alzheimer’s Disease Research Institute

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TitlePharmacological chaperones stabilize retromer to limit APP processing.
Publication TypeJournal Article
Year of Publication2014
AuthorsMecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA
JournalNat Chem Biol
Volume10
Issue6
Pagination443-9
Date Published2014 Jun
ISSN1552-4469
KeywordsAmyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Binding Sites, Carrier Proteins, Cells, Cultured, Endosomes, Hippocampus, Mice, Molecular Docking Simulation, Neurons, Protein Stability, Protein Transport, Small Molecule Libraries, Vesicular Transport Proteins
Abstract

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function. First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP. These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.

DOI10.1038/nchembio.1508
Alternate JournalNat. Chem. Biol.
PubMed ID24747528
PubMed Central IDPMC4076047
Grant ListAG025161 / AG / NIA NIH HHS / United States
AG08702 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
R01 AG025161 / AG / NIA NIH HHS / United States