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dc.contributor.authorGoode, Alice
dc.contributor.authorButler, Kevin
dc.contributor.authorLong, Jed
dc.contributor.authorCavey, James
dc.contributor.authorScott, Daniel
dc.contributor.authorShaw, Barry
dc.contributor.authorSollenberger, Jill
dc.contributor.authorGell, Christopher
dc.contributor.authorJohansen, Terje
dc.contributor.authorOldham, Neil J.
dc.contributor.authorSearle, Mark S.
dc.contributor.authorLayfield, Robert
dc.date.accessioned2017-03-09T11:55:53Z
dc.date.available2017-03-09T11:55:53Z
dc.date.issued2016-05-12
dc.description.abstractGrowing evidence implicates impairment of autophagy as a candidate pathogenic mechanism in the spectrum of neurodegenerative disorders which includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS-FTLD). SQSTM1, which encodes the autophagy receptor SQSTM1/p62, is genetically associated with ALS-FTLD, although to date autophagy-relevant functional defects in disease-associated variants have not been described. A key protein-protein interaction in autophagy is the recognition of a lipidanchored form of LC3 (LC3-II) within the phagophore membrane by SQSTM1, mediated through its LC3- interacting region (LIR), and notably some ALS-FTLD mutations map to this region. Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B. We place our observations on a firm quantitative footing by showing the L341V-mutant LIR is associated with a »3-fold reduction in LC3B binding affinity and using protein NMR we rationalize the structural basis for the effect. This functional deficit is realized in motor neuron-like cells, with the L341V mutant EGFP-mCherry-SQSTM1 less readily incorporated into acidic autophagic vesicles than the wild type. Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore. The oligomeric nature of SQSTM1, which presents multiple LIRs to template growth of the phagophore, potentially gives rise to avidity effects which amplify the relatively modest impact of any single mutation on LC3B binding. Over the lifetime of a neuron, impaired autophagy could expose a vulnerability, which ultimately tips the balance from cell survival toward cell death.en_US
dc.descriptionPublished version. Source at <a href=http://dx.doi.org/10.1080/15548627.2016.1170257> http://dx.doi.org/10.1080/15548627.2016.1170257 </a>en_US
dc.identifier.citationGoode, A. et.al.: Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. Autophagy. 2016;12(7):1094-1104en_US
dc.identifier.cristinIDFRIDAID 1413005
dc.identifier.doi10.1080/15548627.2016.1170257
dc.identifier.issn1554-8627
dc.identifier.issn1554-8635
dc.identifier.urihttps://hdl.handle.net/10037/10507
dc.language.isoengen_US
dc.publisherTaylor & Francisen_US
dc.relation.journalAutophagy
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk mikrobiologi: 715en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical microbiology: 715en_US
dc.subjectALSen_US
dc.subjectAtg8/LC3en_US
dc.subjectautophagyen_US
dc.subjectFTLDen_US
dc.subjectLIRen_US
dc.subjectSQSTM1/p62en_US
dc.titleDefective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLDen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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