Pharmacological chaperones stabilize retromer to limit APP processing

Nature Chemical Biology (Impact Factor: 13). 04/2014; 10(6). DOI: 10.1038/nchembio.1508
Source: PubMed


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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    • "Recently, the retromer has been the target of pharmacological interventions by introducing a small molecular chaperone that decreases amyloidogenic APP processing by stabilizing the retromer complex (Mecozzi et al., 2014). This study demonstrated the neuroprotective capacity of modulators of the APP trafficking pathway. "

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