{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T05:20:08Z","timestamp":1794201608042,"version":"4.8.0"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Investigator"],"award-info":[{"award-number":["Investigator"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,5,12]]},"abstract":"<jats:p>\n                    Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer\u2019s and Parkinson\u2019s diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in\n                    <jats:italic>wobbler<\/jats:italic>\n                    mice, a murine model with a homozygous partial loss-of-function mutation in\n                    <jats:italic>Vps54<\/jats:italic>\n                    (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from\n                    <jats:italic>wobbler<\/jats:italic>\n                    mice. Remarkably, chronic treatment of\n                    <jats:italic>wobbler<\/jats:italic>\n                    mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of\n                    <jats:italic>wobbler<\/jats:italic>\n                    fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1913956117","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T16:41:29Z","timestamp":1588092089000},"page":"10565-10574","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant\n                    <i>wobbler<\/i>\n                    mice, a model of motor neuron degeneration"],"prefix":"10.1073","volume":"117","author":[{"given":"Constance S.","family":"Petit","sequence":"first","affiliation":[{"name":"Department of Molecular Metabolism, Harvard T. H. 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