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

Autor:	Vest RT; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305., Chou CC; Department of Biology, Stanford University, Stanford, CA 94305., Zhang H; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305., Haney MS; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305.; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305., Li L; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304., Laqtom NN; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Institute for Chemistry, Engineering, and Medicine for Human Health, Stanford University, Stanford, CA 94305., Chang B; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304., Shuken S; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305.; Department of Chemistry, Stanford University, Stanford, CA 94305., Nguyen A; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304., Yerra L; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304., Yang AC; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305., Green C; SRI International, Menlo Park, CA 94025., Tanga M; SRI International, Menlo Park, CA 94025., Abu-Remaileh M; Department of Chemical Engineering, Stanford University, Stanford, CA 94305.; Institute for Chemistry, Engineering, and Medicine for Human Health, Stanford University, Stanford, CA 94305., Bassik MC; Institute for Chemistry, Engineering, and Medicine for Human Health, Stanford University, Stanford, CA 94305.; Department of Genetics, Stanford University, Stanford, CA 94305., Frydman J; Department of Biology, Stanford University, Stanford, CA 94305.; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305.; Department of Genetics, Stanford University, Stanford, CA 94305., Luo J; Palo Alto Veterans Institute for Research, Palo Alto, CA 94304., Wyss-Coray T; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305.; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Mar 15; Vol. 119 (11), pp. e2121609119. Date of Electronic Publication: 2022 Mar 08.
DOI:	10.1073/pnas.2121609119
Abstrakt:	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.
Databáze:	MEDLINE
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