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TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A, which represents a \u201csecond hit\u201d that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A\/Tbk1+\/\u2212 mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.<\/jats:p>","DOI":"10.1084\/jem.20180729","type":"journal-article","created":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T14:54:15Z","timestamp":1547218455000},"page":"267-278","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":87,"title":["Heterozygous\n                    <i>Tbk1<\/i>\n                    loss has opposing effects in early and late stages of ALS in mice"],"prefix":"10.1084","volume":"216","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-3146","authenticated-orcid":true,"given":"David","family":"Brenner","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Ulm, Ulm, Germany 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