Knockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy

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dc.authorid0009-0002-8009-4854
dc.contributor.authorPan, Yongli
dc.contributor.authorXin, Wenqiang
dc.contributor.authorWei, Wei
dc.contributor.authorTatenhorst, Lars
dc.contributor.authorGraf, Irina
dc.contributor.authorPopa-Wagner, Aurel
dc.contributor.authorGerner, Stefan T.
dc.contributor.authorHuber, Sabine E.
dc.contributor.authorKılıç, Ertuğrul
dc.contributor.authorHermann, Dirk M.
dc.contributor.authorBähr, Mathias
dc.contributor.authorHuttner, Hagen B.
dc.contributor.authorDoeppner, Thorsten Roland
dc.date.accessioned2024-01-26T10:26:35Z
dc.date.available2024-01-26T10:26:35Z
dc.date.issued2024
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstractBackground: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke. Graphical abstract: [Figure not available: see fulltext.].
dc.description.sponsorshipGeorg-August-Universität Göttingen ; China Scholarship Councilen_US
dc.identifier.citationPan, Y., Xin, W., Wei, W., Tatenhorst, L., Graf, I., Popa-Wagner, A. ... Doeppner, T. R. (2024). Knockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy. Cellular and Molecular Life Sciences, 81(1). https://dx.doi.org/10.1007/s00018-023-05045-7
dc.identifier.doi10.1007/s00018-023-05045-7
dc.identifier.issn1420-682X
dc.identifier.issn1420-9071
dc.identifier.issue1
dc.identifier.pmid38212456
dc.identifier.scopus2-s2.0-85182148055
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.1007/s00018-023-05045-7
dc.identifier.urihttps://hdl.handle.net/20.500.12511/12206
dc.identifier.volume81
dc.identifier.wos001140976800005en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorDoeppner, Thorsten Roland
dc.language.isoen
dc.publisherSpringer Science and Business Media Deutschland GmbH
dc.relation.ispartofCellular and Molecular Life Sciencesen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectAutophagy
dc.subjectLipid Droplets
dc.subjectMicroglia
dc.subjectNEAT1
dc.subjectStroke
dc.titleKnockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy
dc.typeArticle

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