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Multi-Species Phenotypic Screening across Disease Models of Mucolipidosis Type IV

Hadjikyriacou, Andrea, Concannon, John, Sigoillot, Frederic, Antczak, Christophe, Jenkins, Jeremy, Nyfeler, Beat, Jain, Rishi, Tallarico, John and Canham, Steve (2021) Multi-Species Phenotypic Screening across Disease Models of Mucolipidosis Type IV. BioRxiv.


Invertebrate model organisms (mainly the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are valuable tools to bridge the gap between traditional in vitro discovery and preclinical animal models. Invertebrate model organisms are poised to serve as better disease models than 2D cellular monocultures for drug discovery. A strength of model organisms is the opportunity to probe conserved biology such as lysosomal function and offers an attractive approach to exploring autophagy in a natural setting. Invertebrate models are however, not without challenges, such as poor tissue penetration and confidence in a compound’s mechanism of action. To confront these challenges we took advantage of the Novartis’ mechanism-of-action box (MoA Box), a chemogenetic library of well-annotated and drug-like chemical probes. Curious as to how the MoA Box, comprised of chemical probes optimized for mammalian targets, would fair in an invertebrate setting we screened the MoA Box across three different model systems of the lysosomal storage disease Mucolipidosis Type IV (MLIV). MLIV is caused by mutations in the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1) resulting in hyperacidic lysosomes and disregulated autophagy. We leveraged the overlap of screening hits to prioritize efforts and validate that CDK inhibition could resolve several phenotypes of MLIV disease in patient fibroblasts.

Item Type: Article
Keywords: model organisms, lysosomal storage diseases, mucolipidosis IV, chemical genetics, phenotypic screening, drug discovery
Date Deposited: 13 Jul 2021 00:45
Last Modified: 13 Jul 2021 00:45


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