Pharmacological chaperones stabilize retromer to limit APP processing

Vincent J Mecozzi; Diego E Berman; Sabrina Simoes; Chris Vetanovetz; Mehraj R Awal; Vivek M Patel; Remy T Schneider; Gregory A Petsko; Dagmar Ringe; Scott A Small

doi:10.1038/nchembio.1508

Pharmacological chaperones stabilize retromer to limit APP processing

Nat Chem Biol. 2014 Jun;10(6):443-9. doi: 10.1038/nchembio.1508. Epub 2014 Apr 20.

Authors

Affiliations

¹ 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].
² 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].
³ 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.
⁴ 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.
⁵ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Protein Precursor / metabolism*
Animals
Aspartic Acid Endopeptidases / metabolism
Binding Sites
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cells, Cultured
Endosomes / drug effects
Endosomes / metabolism
Hippocampus / cytology
Hippocampus / drug effects
Hippocampus / metabolism
Mice
Molecular Docking Simulation
Neurons / drug effects*
Neurons / metabolism
Protein Stability
Protein Transport
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Vesicular Transport Proteins / genetics
Vesicular Transport Proteins / metabolism*

Substances

Amyloid beta-Protein Precursor
Carrier Proteins
Small Molecule Libraries
VPS29 protein, mouse
Vesicular Transport Proteins
Vps26 protein, mouse
Vps35 protein, mouse
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Bace1 protein, mouse

Associated data

PubChem-Substance/174322461
PubChem-Substance/174322462
PubChem-Substance/174322463

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding