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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,20]]},"abstract":"<jats:p>Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher\u2019s disease, characterized by &lt;15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson\u2019s disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient\u2013derived fibroblasts through an MiT\/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.<\/jats:p>","DOI":"10.1073\/pnas.2320257121","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T12:06:27Z","timestamp":1723809987000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases"],"prefix":"10.1073","volume":"121","author":[{"given":"William C.","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn\u00e9e A.","family":"Massey","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9536-424X","authenticated-orcid":false,"given":"Derek","family":"Rhoades","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-7005","authenticated-orcid":false,"given":"Herman S.","family":"Overkleeft","sequence":"additional","affiliation":[{"name":"Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden 2333 CC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey W.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"e_1_3_4_1_2","volume-title":"Gaucher Disease","author":"Pastores G. 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C. Hou L. A. Massey J. W. Kelly A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE263252. 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