{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:16:10Z","timestamp":1785420970565,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,24]]},"group-title":"Neuroscience","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["NIH R01-AG071777"],"award-info":[{"award-number":["NIH R01-AG071777"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Career Award for Medical Scientists"],"award-info":[{"award-number":["Career Award for Medical Scientists"]}],"id":[{"id":"https:\/\/ror.org\/01d35cw23","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Sleep disruption is an early and prevalent feature of neurodegenerative disease, commonly attributed to neuronal circuit dysfunction or cell loss. However, sleep is tightly coupled to metabolic state, raising the possibility that systemic metabolic abnormalities contribute to disease-associated sleep phenotypes. Using\n                  <jats:italic>Drosophila<\/jats:italic>\n                  models of TDP-43 proteinopathy, we investigated whether peripheral metabolic dysfunction plays a causal role in sleep disruption. We show that TDP-43 expression induces a chronic, starvation-like metabolic state characterized by depletion of peripheral carbohydrate stores despite normal feeding. Restoration of sleep fails to correct these metabolic defects, whereas improving peripheral metabolic state robustly rescues sleep. A modifier screen of \u223c650 RNAi lines identified Salt-inducible kinase 3 (SIK3) as a potent suppressor of both sleep loss and starvation sensitivity. Transcriptomic and spatial metabolomic analyses reveal that SIK3 selectively remodels a peripheral metabolic program centered on the pentose phosphate pathway and redox-associated metabolites without globally restoring energy stores. Together, these findings identify systemic metabolic dysfunction as a key driver of sleep disruption in TDP-43 proteinopathy and highlight peripheral metabolism as a potential therapeutic entry point for sleep dysfunction in neurodegenerative disease.\n                <\/jats:p>","DOI":"10.64898\/2026.02.23.707321","type":"posted-content","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T03:35:11Z","timestamp":1771990511000},"source":"Crossref","is-referenced-by-count":1,"title":["Peripheral metabolic dysfunction drives sleep disruption in TDP-43 proteinopathy"],"prefix":"10.64898","author":[{"given":"Anyara","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Luong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Belfer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Shcherbakova","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Durkin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinky","family":"Kain","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2210-1876","authenticated-orcid":false,"given":"Arjun","family":"Sengupta","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Perlegos","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, 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