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A small molecule mitigates hearing loss in a mouse model of Usher syndrome III

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      Usher syndrome type III (USH3) characterized by progressive deafness, variable balance disorder, and blindness is caused by destabilizing mutations in the gene encoding the clarin-1 protein (CLRN1). Here we report a novel strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1 N48K that involved a cell-based high-throughput screening of small molecules capable of stabilizing CLRN1 N48K, a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure activity relationships. This resulted in the identification of BF844. To test the efficacy of BF844, a mouse model was developed that mimicked the progressive hearing loss of USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the human CLRN1 N48K mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

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        The ability to identify active compounds (³hits²) from large chemical libraries accurately and rapidly has been the ultimate goal in developing high-throughput screening (HTS) assays. The ability to identify hits from a particular HTS assay depends largely on the suitability or quality of the assay used in the screening. The criteria or parameters for evaluating the ³suitability² of an HTS assay for hit identification are not well defined and hence it still remains difficult to compare the quality of assays directly. In this report, a screening window coefficient, called ³Z-factor,² is defined. This coefficient is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment. The Z-factor is a dimensionless, simple statistical characteristic for each HTS assay. The Z-factor provides a useful tool for comparison and evaluation of the quality of assays, and can be utilized in assay optimization and validation.
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          The mammalian unfolded protein response.

          In the endoplasmic reticulum (ER), secretory and transmembrane proteins fold into their native conformation and undergo posttranslational modifications important for their activity and structure. When protein folding in the ER is inhibited, signal transduction pathways, which increase the biosynthetic capacity and decrease the biosynthetic burden of the ER to maintain the homeostasis of this organelle, are activated. These pathways are called the unfolded protein response (UPR). In this review, we briefly summarize principles of protein folding and molecular chaperone function important for a mechanistic understanding of UPR-signaling events. We then discuss mechanisms of signal transduction employed by the UPR in mammals and our current understanding of the remodeling of cellular processes by the UPR. Finally, we summarize data that demonstrate that UPR signaling feeds into decision making in other processes previously thought to be unrelated to ER function, e.g., eukaryotic starvation responses and differentiation programs.

            Author and article information

            [1 ]Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Cleveland, Ohio 44016, USA
            [2 ]Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44016, USA
            [3 ]Neurosciences, Case Western Reserve University, Cleveland, Ohio 44016, USA
            [4 ]Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio 44016, USA
            [5 ]Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 44016, USA
            [6 ]Office of Translation and Innovation, Case Western Reserve University, Cleveland, Ohio 44016, USA
            [7 ]BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, CB10 1XL, UK
            [8 ]Charles River Nederland BV, Darwinweg 24, 2333 CR Leiden, The Netherlands
            Author notes

            Current Address: Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.


            Current address: AstraZeneca, 310, Cambridge Science Park, Milton Road, Cambridge, CB4 0FZ, UK.


            Current address MedImmune, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK.

            Nat Chem Biol
            Nat. Chem. Biol.
            Nature chemical biology
            13 March 2016
            25 April 2016
            June 2016
            25 October 2016
            : 12
            : 6
            : 444-451
            27110679 4871731 10.1038/nchembio.2069 NIHMS767131

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