| Reference | 1. Nat Chem Biol. 2014 Jun;10(6):443-9. doi: 10.1038/nchembio.1508. Epub 2014 Apr
20. <br />
Pharmacological chaperones stabilize retromer to limit APP processing. <br />
Mecozzi VJ(1), Berman DE(2), Simoes S(3), Vetanovetz C(3), Awal MR(4), Patel
VM(3), Schneider RT(3), Petsko GA(5), Ringe D(4), Small SA(3). <br />
Author information: <br />
(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. <br />
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.
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