{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:41:52Z","timestamp":1787020912849,"version":"build-2736575974"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["82101481"],"award-info":[{"award-number":["82101481"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["U21A20362"],"award-info":[{"award-number":["U21A20362"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"crossref","award":["U22A20298"],"award-info":[{"award-number":["U22A20298"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science and Technology Innovation 2030 Major Projects","award":["2022ZD0211600"],"award-info":[{"award-number":["2022ZD0211600"]}]},{"name":"Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital","award":["2022XH032"],"award-info":[{"award-number":["2022XH032"]}]},{"name":"Joint Funds for the Innovation of Science and Technology\uff0cFujian province","award":["2024Y9236"],"award-info":[{"award-number":["2024Y9236"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Neurodegener"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Defective autophagic flux is implicated in Alzheimer's disease (AD), but the molecular mechanisms underlying this process are not fully understood. Salt-inducible kinase 2 (SIK2) is associated with autophagic function. However, its specific involvement in autophagic flux regulation and AD pathogenesis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated hippocampal SIK2 expression and its age-related changes in postmortem AD patients and 5\u2009\u00d7\u2009FAD mice by bioinformatics analysis, immunofluorescence, qPCR, and Western blotting. To investigate the functional role of SIK2, we employed adeno-associated virus-mediated SIK2 knockdown and overexpression in combination with behavioral tests (Morris water maze), electrophysiological recordings (long-term potentiation, LTP), and ultrastructural analysis (electron microscopy) to evaluate cognitive function and synaptic plasticity. Autophagic flux was measured using LC3B\/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence assay, and transmission electron microscopy. Mechanistic insights were gained through co-immunoprecipitation assay, GST-pull down assay, phosphoproteomics, and site-directed mutagenesis. Additionally, phosphorylation-mimetic (S72E) and non-phosphorylatable (S72A) mutants of GABA type A receptor-associated protein-like 2 (GABARAPL2) were intrahippocampally delivered to 5\u2009\u00d7\u2009FAD mice to explore their effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our study identified SIK2 as a critical regulator that is progressively downregulated in hippocampal neurons of AD patients and 5\u2009\u00d7\u2009FAD mice, correlating with spatial memory deficits. Reducing SIK2 levels exacerbates cognitive impairment and amyloid-\u03b2 (A\u03b2) plaque burden in mice, whereas restoring SIK2 levels mitigates these deficits, restores LTP amplitude, reverses synaptic ultrastructural pathology, and reduces A\u03b2 deposition. Mechanistically, SIK2 enhances autophagic flux by phosphorylating GABARAPL2 at Ser72, a modification essential for autophagosome\u2013lysosome fusion. Remarkably, hippocampal delivery of the phosphorylation-mimetic GABARAPL2-S72E mutant replicated the beneficial effects of SIK2, alleviating A\u03b2 pathology and synaptic dysfunction in 5\u2009\u00d7\u2009FAD mice. In contrast, the non-phosphorylatable S72A mutant failed to show any protective effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish the SIK2\u2013GABARAPL2 axis as a novel signaling cascade governing autophagic flux through lysosomal fusion competence. Dysfunction in this axis contributes to A\u03b2 deposition in AD, offering new insights into the pathogenic mechanisms underlying autophagosome\u2013lysosome fusion in AD and highlighting its potential as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-025-00514-4","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T02:12:08Z","timestamp":1761185528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome\u2013lysosome fusion and rescues neurodegeneration in an Alzheimer\u2019s disease model"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-5936","authenticated-orcid":false,"given":"Xiaoman","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziling","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqing","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"issue":"4","key":"514_CR1","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1056\/NEJMra0909142","volume":"362","author":"HW Querfurth","year":"2010","unstructured":"Querfurth HW, LaFerla FM. Alzheimer\u2019s disease. N Engl J Med. 2010;362(4):329\u201344.","journal-title":"N Engl J Med"},{"issue":"10043","key":"514_CR2","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","volume":"388","author":"P Scheltens","year":"2016","unstructured":"Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer\u2019s disease. Lancet. 2016;388(10043):505\u201317.","journal-title":"Lancet"},{"issue":"10","key":"514_CR3","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1038\/nrneurol.2017.111","volume":"13","author":"J Wang","year":"2017","unstructured":"Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease - insights from amyloid-\u03b2 metabolism beyond the brain. Nat Rev Neurol. 2017;13(10):612\u201323.","journal-title":"Nat Rev Neurol"},{"issue":"1","key":"514_CR4","doi-asserted-by":"publisher","first-page":"7998","DOI":"10.1038\/s41467-024-52396-1","volume":"15","author":"X Huang","year":"2024","unstructured":"Huang X, Fowler C, Li Y, Li QX, Sun J, Pan Y, et al. Clearance and transport of amyloid \u03b2 by peripheral monocytes correlate with Alzheimer\u2019s disease progression. Nat Commun. 2024;15(1):7998.","journal-title":"Nat Commun"},{"key":"514_CR5","doi-asserted-by":"publisher","first-page":"1474439","DOI":"10.3389\/fneur.2024.1474439","volume":"15","author":"H Li","year":"2024","unstructured":"Li H, Yao Q, Huang X, Yang X, Yu C. The role and mechanism of A\u03b2 clearance dysfunction in the glymphatic system in Alzheimer\u2019s disease comorbidity. Front Neurol. 2024;15:1474439.","journal-title":"Front Neurol"},{"issue":"6012","key":"514_CR6","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1126\/science.1197623","volume":"330","author":"KG Mawuenyega","year":"2010","unstructured":"Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease. Science. 2010;330(6012):1774.","journal-title":"Science"},{"issue":"4","key":"514_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002591","volume":"22","author":"W Zeng","year":"2024","unstructured":"Zeng W, Li C, Wu R, Yang X, Wang Q, Lin B, et al. Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta. PLoS Biol. 2024;22(4):e3002591.","journal-title":"PLoS Biol"},{"issue":"9","key":"514_CR8","doi-asserted-by":"publisher","first-page":"6287","DOI":"10.1002\/alz.14122","volume":"20","author":"C Zhang","year":"2024","unstructured":"Zhang C, Jia Q, Zhu L, Hou J, Wang X, Li D, et al. Suppressing UBE2N ameliorates Alzheimer\u2019s disease pathology through the clearance of amyloid beta. Alzheimers Dement. 2024;20(9):6287\u2013304.","journal-title":"Alzheimers Dement"},{"issue":"9","key":"514_CR9","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1038\/mp.2017.204","volume":"23","author":"XL Bu","year":"2018","unstructured":"Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, et al. Blood-derived amyloid-\u03b2 protein induces Alzheimer\u2019s disease pathologies. Mol Psychiatry. 2018;23(9):1948\u201356.","journal-title":"Mol Psychiatry"},{"issue":"2","key":"514_CR10","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s00401-017-1721-y","volume":"134","author":"WS Jin","year":"2017","unstructured":"Jin WS, Shen LL, Bu XL, Zhang WW, Chen SH, Huang ZL, et al. Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP\/PS1 mouse model. Acta Neuropathol. 2017;134(2):207\u201320.","journal-title":"Acta Neuropathol"},{"issue":"6","key":"514_CR11","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO Mol Med. 2016;8(6):595\u2013608.","journal-title":"EMBO Mol Med"},{"issue":"7618","key":"514_CR12","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature19323","volume":"537","author":"J Sevigny","year":"2016","unstructured":"Sevigny J, Chiao P, Bussi\u00e8re T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease. Nature. 2016;537(7618):50\u20136.","journal-title":"Nature"},{"issue":"6","key":"514_CR13","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nrn3961","volume":"16","author":"FM Menzies","year":"2015","unstructured":"Menzies FM, Fleming A, Rubinsztein DC. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci. 2015;16(6):345\u201357.","journal-title":"Nat Rev Neurosci"},{"key":"514_CR14","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neulet.2018.05.017","volume":"697","author":"KM Chung","year":"2019","unstructured":"Chung KM, Hern\u00e1ndez N, Sproul AA, Yu WH. Alzheimer\u2019s disease and the autophagic-lysosomal system. Neurosci Lett. 2019;697:49\u201358.","journal-title":"Neurosci Lett"},{"issue":"30","key":"514_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202402030","volume":"11","author":"P Deng","year":"2024","unstructured":"Deng P, Fan T, Gao P, Peng Y, Li M, Li J, et al. SIRT5-mediated desuccinylation of RAB7A protects against cadmium-induced Alzheimer\u2019s disease-like pathology by restoring autophagic flux. Adv Sci. 2024;11(30):e2402030.","journal-title":"Adv Sci"},{"issue":"5","key":"514_CR16","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1080\/15548627.2023.2287925","volume":"20","author":"H Heo","year":"2024","unstructured":"Heo H, Park H, Lee MS, Kim J, Kim J, Jung SY, et al. TRIM22 facilitates autophagosome\u2013lysosome fusion by mediating the association of GABARAPs and PLEKHM1. Autophagy. 2024;20(5):1098\u2013113.","journal-title":"Autophagy"},{"issue":"6","key":"514_CR17","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s41593-022-01084-8","volume":"25","author":"JH Lee","year":"2022","unstructured":"Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, et al. Faulty autolysosome acidification in Alzheimer\u2019s disease mouse models induces autophagic build-up of A\u03b2 in neurons, yielding senile plaques. Nat Neurosci. 2022;25(6):688\u2013701.","journal-title":"Nat Neurosci"},{"key":"514_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/cells7050037","author":"A Metaxakis","year":"2018","unstructured":"Metaxakis A, Ploumi C, Tavernarakis N. Autophagy in age-associated neurodegeneration. Cells. 2018. https:\/\/doi.org\/10.3390\/cells7050037.","journal-title":"Cells"},{"issue":"1","key":"514_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-024-01443-6","volume":"16","author":"HM Terron","year":"2024","unstructured":"Terron HM, Parikh SJ, Abdul-Hay SO, Sahara T, Kang D, Dickson DW, et al. Prominent tauopathy and intracellular \u03b2-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis. Alzheimers Res Ther. 2024;16(1):70.","journal-title":"Alzheimers Res Ther"},{"issue":"1","key":"514_CR20","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41398-021-01427-2","volume":"11","author":"L Zhang","year":"2021","unstructured":"Zhang L, Fang Y, Zhao X, Zheng Y, Ma Y, Li S, et al. Bruce silencing leads to axonal dystrophy by repressing autophagosome\u2013lysosome fusion in Alzheimer\u2019s disease. Transl Psychiatry. 2021;11(1):421.","journal-title":"Transl Psychiatry"},{"key":"514_CR21","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.neures.2015.08.002","volume":"103","author":"M Kurosawa","year":"2016","unstructured":"Kurosawa M, Matsumoto G, Sumikura H, Hatsuta H, Murayama S, Sakurai T, et al. Serine 403-phosphorylated p62\/SQSTM1 immunoreactivity in inclusions of neurodegenerative diseases. Neurosci Res. 2016;103:64\u201370.","journal-title":"Neurosci Res"},{"issue":"50","key":"514_CR22","doi-asserted-by":"publisher","first-page":"eade0764","DOI":"10.1126\/sciadv.ade0764","volume":"8","author":"H Yang","year":"2022","unstructured":"Yang H, Oh CK, Amal H, Wishnok JS, Lewis S, Schahrer E, et al. Mechanistic insight into female predominance in Alzheimer\u2019s disease based on aberrant protein S-nitrosylation of C3. Sci Adv. 2022;8(50):eade0764.","journal-title":"Sci Adv"},{"issue":"12","key":"514_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107908","volume":"300","author":"K Goldin-Azulay","year":"2024","unstructured":"Goldin-Azulay K, Fraiberg M, Trofimyuk O, Levin Y, Reuven N, Kopitman E, et al. Multiplex genomic tagging of mammalian ATG8s to study autophagy. J Biol Chem. 2024;300(12):107908.","journal-title":"J Biol Chem"},{"issue":"2","key":"514_CR24","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s42977-022-00119-2","volume":"73","author":"JCY Chan","year":"2022","unstructured":"Chan JCY, Gorski SM. Unlocking the gate to GABARAPL2. Biol Futura. 2022;73(2):157\u201369.","journal-title":"Biol Futura"},{"issue":"Pt 5","key":"514_CR25","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1107\/S2053230X21004489","volume":"77","author":"K Scicluna","year":"2021","unstructured":"Scicluna K, Dewson G, Czabotar PE, Birkinshaw RW. A new crystal form of GABARAPL2. Acta Crystallogr F Struct Biol Commun. 2021;77(Pt 5):140\u20137.","journal-title":"Acta Crystallogr F Struct Biol Commun"},{"issue":"12","key":"514_CR26","doi-asserted-by":"publisher","first-page":"3961","DOI":"10.1096\/fj.201600698R","volume":"30","author":"MB Schaaf","year":"2016","unstructured":"Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3\/GABARAP family proteins: autophagy-(un)related functions. FASEB J. 2016;30(12):3961\u201378.","journal-title":"FASEB J"},{"issue":"16","key":"514_CR27","doi-asserted-by":"publisher","first-page":"jcs259725","DOI":"10.1242\/jcs.259725","volume":"136","author":"JL Nieto-Torres","year":"2023","unstructured":"Nieto-Torres JL, Zaretski S, Liu T, Adams PD, Hansen M. Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control. J Cell Sci.\u00a02023;136(16):jcs259725.","journal-title":"J Cell Sci"},{"issue":"8","key":"514_CR28","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.3390\/cells11081330","volume":"11","author":"NY Park","year":"2022","unstructured":"Park NY, Jo DS, Cho DH. Post-translational modifications of ATG4B in the regulation of autophagy. Cells.\u00a02022;11(8):1330.","journal-title":"Cells"},{"issue":"13","key":"514_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.166987","volume":"433","author":"M Wirth","year":"2021","unstructured":"Wirth M, Mouilleron S, Zhang W, Sj\u00f8ttem E, Princely Abudu Y, Jain A, et al. Phosphorylation of the LIR domain of SCOC modulates ATG8 binding affinity and specificity. J Mol Biol. 2021;433(13):166987.","journal-title":"J Mol Biol"},{"issue":"7302","key":"514_CR30","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature09204","volume":"466","author":"C Behrends","year":"2010","unstructured":"Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature. 2010;466(7302):68\u201376.","journal-title":"Nature"},{"issue":"4","key":"514_CR31","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","volume":"186","author":"DM Wilson 3rd","year":"2023","unstructured":"Wilson DM 3rd, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186(4):693\u2013714.","journal-title":"Cell"},{"issue":"5","key":"514_CR32","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1016\/S0021-9258(17)49883-8","volume":"295","author":"BK Shrestha","year":"2020","unstructured":"Shrestha BK, Skytte Rasmussen M, Abudu YP, Bruun JA, Larsen KB, Alemu EA, et al. NIMA-related kinase 9-mediated phosphorylation of the microtubule-associated LC3B protein at Thr-50 suppresses selective autophagy of p62\/sequestosome 1. J Biol Chem. 2020;295(5):1240\u201360.","journal-title":"J Biol Chem"},{"issue":"187","key":"514_CR33","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002355","volume":"4","author":"H Weidberg","year":"2011","unstructured":"Weidberg H, Elazar Z. TBK1 mediates crosstalk between the innate immune response and autophagy. Sci Signal. 2011;4(187):pe39.","journal-title":"Sci Signal"},{"issue":"1","key":"514_CR34","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201948317","volume":"21","author":"L Herhaus","year":"2020","unstructured":"Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, et al. TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. EMBO Rep. 2020;21(1):e48317.","journal-title":"EMBO Rep"},{"issue":"8","key":"514_CR35","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1111\/jog.15714","volume":"49","author":"D Hu","year":"2023","unstructured":"Hu D, Du J, Xing Y, Cheng Y, He R, Liang X, et al. SIK2: a critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer. J Obstet Gynaecol Res. 2023;49(8):2000\u20139.","journal-title":"J Obstet Gynaecol Res"},{"issue":"1","key":"514_CR36","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1002\/1878-0261.12838","volume":"15","author":"XM Dai","year":"2021","unstructured":"Dai XM, Zhang YH, Lin XH, Huang XX, Zhang Y, Xue CR, et al. SIK2 represses AKT\/GSK3\u03b2\/\u03b2-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases. Mol Oncol. 2021;15(1):228\u201345.","journal-title":"Mol Oncol"},{"issue":"3","key":"514_CR37","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.bbrc.2018.11.177","volume":"508","author":"F Negoita","year":"2019","unstructured":"Negoita F, S\u00e4ll J, Mor\u00e9n B, Stenkula K, G\u00f6ransson O. Salt-inducible kinase 2 regulates TFEB and is required for autophagic flux in adipocytes. Biochem Biophys Res Commun. 2019;508(3):775\u20139.","journal-title":"Biochem Biophys Res Commun"},{"key":"514_CR38","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.683898","volume":"13","author":"R Zhang","year":"2022","unstructured":"Zhang R, Liu Y, Zhong W, Hu Z, Wu C, Ma M, et al. SIK2 improving mitochondrial autophagy restriction induced by cerebral ischemia-reperfusion in rats. Front Pharmacol. 2022;13:683898.","journal-title":"Front Pharmacol"},{"issue":"1","key":"514_CR39","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.neuron.2010.12.004","volume":"69","author":"T Sasaki","year":"2011","unstructured":"Sasaki T, Takemori H, Yagita Y, Terasaki Y, Uebi T, Horike N, et al. SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB. Neuron. 2011;69(1):106\u201319.","journal-title":"Neuron"},{"key":"514_CR40","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.624429","volume":"11","author":"Y Liu","year":"2020","unstructured":"Liu Y, Tang W, Ji C, Gu J, Chen Y, Huang J, et al. The selective SIK2 inhibitor ARN-3236 produces strong antidepressant-like efficacy in mice via the hippocampal CRTC1-CREB-BDNF pathway. Front Pharmacol. 2020;11:624429.","journal-title":"Front Pharmacol"},{"key":"514_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2023.109437","volume":"227","author":"J Huang","year":"2023","unstructured":"Huang J, Fan H, Chen YM, Wang CN, Guan W, Li WY, et al. The salt-inducible kinases inhibitor HG-9-91-01 exhibits antidepressant-like actions in mice exposed to chronic unpredictable mild stress. Neuropharmacology. 2023;227:109437.","journal-title":"Neuropharmacology"},{"key":"514_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2024.114972","volume":"465","author":"XM Cai","year":"2024","unstructured":"Cai XM, Sun XY, Li R, Wang PJ, Qiu JC, Ge YX, et al. The hippocampal salt-inducible kinase 2-CREB-regulated transcription co-activator 1 system mediates the antidepressant actions of paroxetine in mice. Behav Brain Res. 2024;465:114972.","journal-title":"Behav Brain Res"},{"issue":"45","key":"514_CR43","doi-asserted-by":"publisher","first-page":"13618","DOI":"10.1021\/acs.jafc.1c04907","volume":"69","author":"G Zhou","year":"2021","unstructured":"Zhou G, Hu Y, Wang A, Guo M, Du Y, Gong Y, et al. Fluoride stimulates anxiety- and depression-like behaviors associated with SIK2-CRTC1 signaling dysfunction. J Agric Food Chem. 2021;69(45):13618\u201327.","journal-title":"J Agric Food Chem"},{"issue":"8","key":"514_CR44","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.biopsych.2018.10.004","volume":"85","author":"B Jiang","year":"2019","unstructured":"Jiang B, Wang H, Wang JL, Wang YJ, Zhu Q, Wang CN, et al. Hippocampal salt-inducible kinase 2 plays a role in depression via the CREB-regulated transcription coactivator 1-cAMP response element binding-brain-derived neurotrophic factor pathway. Biol Psychiatry. 2019;85(8):650\u201366.","journal-title":"Biol Psychiatry"},{"issue":"6","key":"514_CR45","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/s41386-023-01775-1","volume":"49","author":"X Dai","year":"2024","unstructured":"Dai X, Lin A, Zhuang L, Zeng Q, Cai L, Wei Y, et al. Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer\u2019s disease. Neuropsychopharmacology. 2024;49(6):942\u201352.","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"514_CR46","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s00401-011-0896-x","volume":"123","author":"R Sanchez-Varo","year":"2012","unstructured":"Sanchez-Varo R, Trujillo-Estrada L, Sanchez-Mejias E, Torres M, Baglietto-Vargas D, Moreno-Gonzalez I, et al. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer\u2019s mice hippocampus. Acta Neuropathol. 2012;123(1):53\u201370.","journal-title":"Acta Neuropathol"},{"issue":"2","key":"514_CR47","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1093\/jnen\/64.2.113","volume":"64","author":"RA Nixon","year":"2005","unstructured":"Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64(2):113\u201322.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"10","key":"514_CR48","doi-asserted-by":"publisher","first-page":"2680","DOI":"10.1080\/15548627.2020.1823124","volume":"17","author":"X Tian","year":"2021","unstructured":"Tian X, Teng J, Chen J. New insights regarding SNARE proteins in autophagosome\u2013lysosome fusion. Autophagy. 2021;17(10):2680\u20138.","journal-title":"Autophagy"},{"issue":"1","key":"514_CR49","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.molcel.2014.11.006","volume":"57","author":"DG McEwan","year":"2015","unstructured":"McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, et al. PLEKHM1 regulates autophagosome\u2013lysosome fusion through HOPS complex and LC3\/GABARAP proteins. Mol Cell. 2015;57(1):39\u201354.","journal-title":"Mol Cell"},{"issue":"8","key":"514_CR50","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1091\/mbc.e13-08-0447","volume":"25","author":"P Jiang","year":"2014","unstructured":"Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, et al. The HOPS complex mediates autophagosome\u2013lysosome fusion through interaction with syntaxin 17. Mol Biol Cell. 2014;25(8):1327\u201337.","journal-title":"Mol Biol Cell"},{"issue":"7","key":"514_CR51","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1242\/jcs.196352","volume":"130","author":"S Nakamura","year":"2017","unstructured":"Nakamura S, Yoshimori T. New insights into autophagosome\u2013lysosome fusion. J Cell Sci. 2017;130(7):1209\u201316.","journal-title":"J Cell Sci"},{"issue":"1","key":"514_CR52","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1080\/15548627.2021.1909407","volume":"18","author":"M Licheva","year":"2022","unstructured":"Licheva M, Raman B, Kraft C, Reggiori F. Phosphoregulation of the autophagy machinery by kinases and phosphatases. Autophagy. 2022;18(1):104\u201323.","journal-title":"Autophagy"},{"issue":"12","key":"514_CR53","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1111\/j.1365-2443.2008.01238.x","volume":"13","author":"NN Noda","year":"2008","unstructured":"Noda NN, Kumeta H, Nakatogawa H, Satoo K, Adachi W, Ishii J, et al. Structural basis of target recognition by Atg8\/LC3 during selective autophagy. Genes Cells. 2008;13(12):1211\u20138.","journal-title":"Genes Cells"},{"issue":"18","key":"514_CR54","doi-asserted-by":"publisher","first-page":"3691","DOI":"10.1038\/emboj.2012.225","volume":"31","author":"C Kraft","year":"2012","unstructured":"Kraft C, Kijanska M, Kalie E, Siergiejuk E, Lee SS, Semplicio G, et al. Binding of the Atg1\/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J. 2012;31(18):3691\u2013703.","journal-title":"EMBO J"},{"issue":"47","key":"514_CR55","doi-asserted-by":"publisher","first-page":"39275","DOI":"10.1074\/jbc.M112.378109","volume":"287","author":"EA Alemu","year":"2012","unstructured":"Alemu EA, Lamark T, Torgersen KM, Birgisdottir AB, Larsen KB, Jain A, et al. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J Biol Chem. 2012;287(47):39275\u201390.","journal-title":"J Biol Chem"},{"issue":"12","key":"514_CR56","doi-asserted-by":"publisher","first-page":"10365","DOI":"10.1007\/s12035-024-04177-6","volume":"61","author":"Q Hou","year":"2024","unstructured":"Hou Q, Hu W, Peterson L, Gilbert J, Liu R, Man HY. SIK1 downregulates synaptic AMPA receptors and contributes to cognitive defects in Alzheimer\u2019s disease. Mol Neurobiol. 2024;61(12):10365\u201380.","journal-title":"Mol Neurobiol"},{"issue":"5","key":"514_CR57","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.366","volume":"4","author":"J Zhu","year":"2023","unstructured":"Zhu J, Li C, Wang P, Liu Y, Li Z, Chen Z, et al. Deficiency of salt-inducible kinase 2 (SIK2) promotes immune injury by inhibiting the maturation of lymphocytes. MedComm. 2023;4(5):e366.","journal-title":"MedComm"},{"key":"514_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100428","volume":"296","author":"NJ Darling","year":"2021","unstructured":"Darling NJ, Arthur JSC, Cohen P. Salt-inducible kinases are required for the IL-33-dependent secretion of cytokines and chemokines in mast cells. J Biol Chem. 2021;296:100428.","journal-title":"J Biol Chem"},{"issue":"6","key":"514_CR59","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202402628R","volume":"39","author":"S Han","year":"2025","unstructured":"Han S, Xiang X, Zhang X, Ou L, Liu Q, Xu X, et al. Activation of SIK2 inhibits gluconeogenesis and alleviates lipogenesis-induced inflammatory response by SIK2-CRTC2-ACC1 in hepatocytes of large yellow croaker (Larimichthys crocea). FASEB J. 2025;39(6):e70393.","journal-title":"FASEB J"},{"key":"514_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbrc.2022.02.015","volume":"599","author":"T Wang","year":"2022","unstructured":"Wang T, Zheng R, Sun S. Drug repurposing: Escitalopram attenuates acute lung injury by inhibiting the SIK2\/ HDAC4\/ NF-\u03baB signaling cascade. Biochem Biophys Res Commun. 2022;599:1\u20138.","journal-title":"Biochem Biophys Res Commun"},{"issue":"1","key":"514_CR61","doi-asserted-by":"publisher","first-page":"10559","DOI":"10.1038\/s41598-023-37340-5","volume":"13","author":"M Vav\u00e1kov\u00e1","year":"2023","unstructured":"Vav\u00e1kov\u00e1 M, Hofwimmer K, Laurencikiene J, G\u00f6ransson O. Mechanism of TNF\u03b1-induced downregulation of salt-inducible kinase 2 in adipocytes. Sci Rep. 2023;13(1):10559.","journal-title":"Sci Rep"},{"issue":"18","key":"514_CR62","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.3390\/cells13181565","volume":"13","author":"MS T\u00fcrk\u00fcner","year":"2024","unstructured":"T\u00fcrk\u00fcner MS, Yaz\u0131c\u0131 A, \u00d6zcan F. SIK2 controls the homeostatic character of the POMC secretome acutely in response to pharmacological ER stress induction. Cells.\u00a02024;13(18):1565.","journal-title":"Cells"},{"issue":"12","key":"514_CR63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102644","volume":"298","author":"M van Gijsel-Bonnello","year":"2022","unstructured":"van Gijsel-Bonnello M, Darling NJ, Tanaka T, Di Carmine S, Marchesi F, Thomson S, et al. Salt-inducible kinase 2 regulates fibrosis during bleomycin-induced lung injury. J Biol Chem. 2022;298(12):102644.","journal-title":"J Biol Chem"},{"key":"514_CR64","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102571","volume":"59","author":"S Misra","year":"2023","unstructured":"Misra S, Lee TJ, Sebastian A, McGuigan J, Liao C, Koo I, et al. Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation. Redox Biol. 2023;59:102571.","journal-title":"Redox Biol"}],"container-title":["Translational Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40035-025-00514-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40035-025-00514-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40035-025-00514-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T03:37:07Z","timestamp":1761190627000},"score":1,"resource":{"primary":{"URL":"https:\/\/translationalneurodegeneration.biomedcentral.com\/articles\/10.1186\/s40035-025-00514-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["514"],"URL":"https:\/\/doi.org\/10.1186\/s40035-025-00514-4","relation":{},"ISSN":["2047-9158"],"issn-type":[{"value":"2047-9158","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]},"assertion":[{"value":"22 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All protocols and procedures of the animal experiments in this study were reviewed and approved by the Institutional Animal Care and Use Committee of the Fujian Medical University (IACUC FJMU 2022\u20130859).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors read and approved the final manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors have no potential conflicts of interests or financial issues to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"53"}}