{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:43:06Z","timestamp":1781898186979,"version":"3.54.5"},"reference-count":85,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271450"],"award-info":[{"award-number":["82271450"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301599"],"award-info":[{"award-number":["82301599"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt\u2010inducible kinase 2 (SIK2), a member of the AMP\u2010activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In our work, we used both in\u00a0vivo and in\u00a0vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT\u2010qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK\u20108 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh\u2010SIK2) were injected into the lateral ventricle of ALS mice at 60\u2009days of age. Motor performance was evaluated by the rotarod test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1<jats:sup>G93A<\/jats:sup> transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In\u00a0vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy\u2010mediated clearance of mutant SOD1 aggregates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy\u2010mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70341","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T04:51:12Z","timestamp":1743223872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of Salt\u2010Inducible Kinase 2 Protects Motor Neurons From Degeneration in <scp>ALS<\/scp> by Activating Autophagic Flux and Enhancing <scp>mTORC1<\/scp> Activity"],"prefix":"10.1111","volume":"31","author":[{"given":"Weiwei","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"},{"name":"Department of Neurology The Second Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Life Science and Technology of China, Department of Neurology The First Affiliated Hospital of USTC  Hefei P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingli","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohua","family":"Cong","sequence":"additional","affiliation":[{"name":"Department of Neurology Shanghai No. 9 People's Hospital, Shanghai Jiaotong University School of Medicine  Shanghai P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5062-8846","authenticated-orcid":false,"given":"Honglin","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Harbin Medical University  Harbin P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2017.03.030"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2016-315018"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12351"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.3389\/fncel.2013.00239","article-title":"Characterization of Wnt\/Beta\u2010Catenin and BMP\/Smad Signaling Pathways in an In\u00a0Vitro Model of Amyotrophic Lateral Sclerosis","volume":"7","author":"Pinto C.","year":"2013","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24012"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115402109"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1125-6"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1361-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.03.047"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2015.0820"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3182160690"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1149-y"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201694401"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.06.026"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.06.045"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00428-5"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.027"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1505155"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.511212"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.4.14541"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.06.018"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-13-0182-T"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.10.004"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.12.004"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202462"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00018"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.431239"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00380-16"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.11.177"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8209258"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.06.040"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2011.10.022"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104648"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.08.009"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.013"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105457"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-015-9165-7"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.04922.x"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10529-007-9595-z"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2005.02.004"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.1.2.1697"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.03.048"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.4600"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.09.018"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12838"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2010.11.003"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-130052"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-12-1249"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.262"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2004.07.009"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3565"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.03.008"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1432327"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.79"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5524"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1830709"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq257"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608787200"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.01.021"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2005.04.020"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06388.x"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609743200"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.28784"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.11"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2757"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.125773"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.06.017"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06463.x"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.03.035"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.22526"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0281-x"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1516725113"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2015.10.006"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.18388\/pb.2016_37"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00263"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00708-5"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215450109"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2A0715-307R"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008175"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1412308111"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20141165"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf3962"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-033131"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.375"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70341","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T15:55:03Z","timestamp":1744818903000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":85,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1111\/cns.70341"],"URL":"https:\/\/doi.org\/10.1111\/cns.70341","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2024-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70341"}}