title: Pharmacological chaperones stabilize retromer to limit APP processing.
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.
authors.affiliation: 1] Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA. [2] Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Masschusetts, USA. [3].
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Mecozzi
authors.affiliation: 1] The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA. [2].
authors.forename: Diego E
authors.identifier: 0000000211313876
authors.initials: DE
authors.lastname: Berman
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Simoes
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Vetanovetz
authors.affiliation: 1] Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA. [2] Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Masschusetts, USA.
authors.forename: Mehraj R
authors.initials: MR
authors.lastname: Awal
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Patel
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Remy T
authors.initials: RT
authors.lastname: Schneider
authors.affiliation: 1] Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA. [2] Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Masschusetts, USA. [3] Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, New York, New York, USA. [4] Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA. [5] Department of Neurology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: 1] Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA. [2] Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Masschusetts, USA.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D054852:Small Molecule Libraries; C503111:VPS29 protein, mouse; D033921:Vesicular Transport Proteins; C089989:Vps26 protein, mouse; C101274:Vps35 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
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