Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration

SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for br...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2022-03, Vol.119 (11), p.e2121609119-e2121609119
Main Authors:	Vest, Ryan T, Chou, Ching-Chieh, Zhang, Hui, Haney, Michael S, Li, Lulin, Laqtom, Nouf N, Chang, Betty, Shuken, Steven, Nguyen, Andy, Yerra, Lakshmi, Yang, Andrew C, Green, Carol, Tanga, Mary, Abu-Remaileh, Monther, Bassik, Michael C, Frydman, Judith, Luo, Jian, Wyss-Coray, Tony
Format:	Article
Language:	eng
Subjects:	Acidification Aging Animal models Animals Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology Bioavailability Biological Sciences Biomarkers Brain - drug effects Brain - metabolism Cell lines Cognitive ability CRISPR Dementia disorders Disease Models, Animal Disease Susceptibility Dopamine receptors Drug Development Drug screening Frontotemporal dementia Gene Expression Profiling Genomes Humans Inflammation Lysosomal storage diseases Lysosomes - drug effects Mice Movement disorders MPTP Neurodegeneration Neurodegenerative diseases Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - etiology Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - pathology Neurons - drug effects Neurons - metabolism Neuroprotection Parkinson's disease Piperidine Protein interaction Smad Proteins - agonists Target recognition Therapeutic targets Urea
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Summary:	SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts. In this work, we find that the antiinflammatory and neuroprotective compound, discovered via a phenotypic screen, imparts its beneficial effects by targeting the lysosome and restoring its function. This is established using a genome-wide CRISPRi target identification screen and then confirmed using a variety of lysosome-targeted studies. The resulting small molecule from this study represents a potential treatment for neurodegenerative diseases as well as a research tool for the study of lysosomes in disease.
ISSN:	0027-8424 1091-6490