{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T21:41:58Z","timestamp":1763415718837,"version":"3.41.2"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01NS101745"],"award-info":[{"award-number":["R01NS101745"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical systems, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing \u03b3-secretase activity. Mouse genetic analysis highlighted the importance of Presenilin (PS) in learning and memory, synaptic plasticity and neurotransmitter release, and neuronal survival, and Drosophila studies further demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, molecular pathways that interact with PS in neuronal survival remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila \u00a0Psn model that exhibits age-dependent neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, we tested top ranked candidate genes by selective knockdown (KD) of each gene in neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid transport and metabolism. Specifically, neuron-specific KD of lipophorin receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that LpRs modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.<\/jats:p>","DOI":"10.1093\/genetics\/iyad202","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T01:55:08Z","timestamp":1700790908000},"source":"Crossref","is-referenced-by-count":6,"title":["Lipophorin receptors genetically modulate neurodegeneration caused by reduction of <i>Psn<\/i> expression in the aging <i>Drosophila<\/i> brain"],"prefix":"10.1093","volume":"226","author":[{"given":"Jongkyun","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Neurology, Brigham and Women's Hospital , Harvard Medical School, Boston, MA 02115 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9494-1378","authenticated-orcid":false,"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women's Hospital , Harvard Medical School, Boston, MA 02115 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology , Cambridge, MA 02139 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Illinois at Urbana-Champaign , Champaign, IL 61801 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie","family":"Berger","sequence":"additional","affiliation":[{"name":"Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology , Cambridge, MA 02139 , USA"},{"name":"Department of Mathematics, Massachusetts Institute of Technology , Cambridge, MA 02139 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Perrimon","sequence":"additional","affiliation":[{"name":"Department of Genetics , Harvard Medical School, Boston, MA 02115, USA"},{"name":"Howard Hughes Medical Institute , Boston, MA 02115 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1160-7118","authenticated-orcid":false,"given":"Jie","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women's Hospital , Harvard Medical School, Boston, MA 02115 , USA"},{"name":"Program in Neuroscience, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"issue":"3","key":"2024091716323640900_iyad202-B1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/S1474-4422(10)70323-9","article-title":"Pre-dementia clinical 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