{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:27:18Z","timestamp":1782275238658,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009258","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:00:00Z","timestamp":1609113600000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012207","name":"Grace Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012207","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM130317"],"award-info":[{"award-number":["R35GM130317"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Mutations in human<jats:italic>N<\/jats:italic>-glycanase 1 (<jats:italic>NGLY1<\/jats:italic>) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as<jats:italic>NGLY1<\/jats:italic>deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called \"nuclear factor erythroid 2-like 1\" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its<jats:italic>in vivo<\/jats:italic>consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the<jats:italic>Drosophila<\/jats:italic>larval intestine results in a severe reduction in the level of AMP-activated protein kinase \u03b1 (AMPK\u03b1), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality.<jats:italic>Ngly1<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup>mouse embryonic fibroblasts and<jats:italic>NGLY1<\/jats:italic>deficiency patient fibroblasts also show reduced<jats:italic>AMPK\u03b1<\/jats:italic>levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPK\u03b1 level and impaired energy metabolism observed in<jats:italic>NGLY1<\/jats:italic>deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in<jats:italic>NGLY1<\/jats:italic>deficiency and suggest AMPK signaling as a therapeutic target in this disease.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009258","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T18:47:31Z","timestamp":1607971651000},"page":"e1009258","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["A conserved role for AMP-activated protein kinase in NGLY1 deficiency"],"prefix":"10.1371","volume":"16","author":[{"given":"Seung 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