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dc.contributor.authorLu, Yubing
dc.contributor.authorWest, Ryan J. H.
dc.contributor.authorPons, Marine
dc.contributor.authorSweeney, Sean T.
dc.contributor.authorGao, Fen-Biao
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:54Z
dc.date.available2022-08-23T16:49:54Z
dc.date.issued2020-08-26
dc.date.submitted2020-09-29
dc.identifier.citation<p>Lu Y, West RJH, Pons M, Sweeney ST, Gao FB. Ik2/TBK1 and Hook/Dynein, an adaptor complex for early endosome transport, are genetic modifiers of FTD-associated mutant CHMP2B toxicity in Drosophila. Sci Rep. 2020 Aug 26;10(1):14221. doi: 10.1038/s41598-020-71097-5. PMID: 32848189; PMCID: PMC7450086. <a href="https://doi.org/10.1038/s41598-020-71097-5">Link to article on publisher's site</a></p>
dc.identifier.issn2045-2322 (Linking)
dc.identifier.doi10.1038/s41598-020-71097-5
dc.identifier.pmid32848189
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41554
dc.description.abstractMutations in CHMP2B, encoding a protein in the endosomal sorting complexes required for transport (ESCRT) machinery, causes frontotemporal dementia linked to chromosome 3 (FTD3). FTD, the second most common form of pre-senile dementia, can also be caused by genetic mutations in other genes, including TANK-binding kinase 1 (TBK1). How FTD-causing disease genes interact is largely unknown. We found that partial loss function of Ik2, the fly homologue of TBK1 also known as I-kappaB kinase epsilon (IKKepsilon), enhanced the toxicity of mutant CHMP2B in the fly eye and that Ik2 overexpression suppressed the effect of mutant CHMP2B in neurons. Partial loss of function of Spn-F, a downstream phosphorylation target of Ik2, greatly enhanced the mutant CHMP2B phenotype. An interactome analysis to understand cellular processes regulated by Spn-F identified a network of interacting proteins including Spn-F, Ik2, dynein light chain, and Hook, an adaptor protein in early endosome transport. Partial loss of function of dynein light chain or Hook also enhanced mutant CHMP2B toxicity. These findings identify several evolutionarily conserved genes, including ik2/TBK1, cut up (encoding dynein light chain) and hook, as genetic modifiers of FTD3-associated mutant CHMP2B toxicity and implicate early endosome transport as a potential contributing pathway in FTD.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32848189&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectEvolution
dc.subjectNeuroscience
dc.subjectEcology and Evolutionary Biology
dc.subjectGenetics and Genomics
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectNeuroscience and Neurobiology
dc.titleIk2/TBK1 and Hook/Dynein, an adaptor complex for early endosome transport, are genetic modifiers of FTD-associated mutant CHMP2B toxicity in Drosophila
dc.typeJournal Article
dc.source.journaltitleScientific reports
dc.source.volume10
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5371&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4344
dc.identifier.contextkey19587015
refterms.dateFOA2022-08-23T16:49:54Z
html.description.abstract<p>Mutations in CHMP2B, encoding a protein in the endosomal sorting complexes required for transport (ESCRT) machinery, causes frontotemporal dementia linked to chromosome 3 (FTD3). FTD, the second most common form of pre-senile dementia, can also be caused by genetic mutations in other genes, including TANK-binding kinase 1 (TBK1). How FTD-causing disease genes interact is largely unknown. We found that partial loss function of Ik2, the fly homologue of TBK1 also known as I-kappaB kinase epsilon (IKKepsilon), enhanced the toxicity of mutant CHMP2B in the fly eye and that Ik2 overexpression suppressed the effect of mutant CHMP2B in neurons. Partial loss of function of Spn-F, a downstream phosphorylation target of Ik2, greatly enhanced the mutant CHMP2B phenotype. An interactome analysis to understand cellular processes regulated by Spn-F identified a network of interacting proteins including Spn-F, Ik2, dynein light chain, and Hook, an adaptor protein in early endosome transport. Partial loss of function of dynein light chain or Hook also enhanced mutant CHMP2B toxicity. These findings identify several evolutionarily conserved genes, including ik2/TBK1, cut up (encoding dynein light chain) and hook, as genetic modifiers of FTD3-associated mutant CHMP2B toxicity and implicate early endosome transport as a potential contributing pathway in FTD.</p>
dc.identifier.submissionpathoapubs/4344
dc.contributor.departmentDepartment of Neurology
dc.source.pages14221


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© The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.