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dc.contributor.authorLu, Mengen
dc.contributor.authorBanetta, Lucaen
dc.contributor.authorYoung, Laurence Jen
dc.contributor.authorSmith, Edward Jen
dc.contributor.authorBates, Gillian Pen
dc.contributor.authorZaccone, Alessioen
dc.contributor.authorKaminski, Gabrieleen
dc.contributor.authorTunnacliffe, Alanen
dc.contributor.authorKaminski, Clemensen
dc.date.accessioned2018-12-19T00:30:50Z
dc.date.available2018-12-19T00:30:50Z
dc.date.issued2019-01en
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287169
dc.description.abstractThe mechanisms leading to self-assembly of misfolded proteins into amyloid aggregates have been studied extensively in the test tube under well-controlled conditions. However, to what extent these processes are representative of those in the cellular environment remains unclear. Using super-resolution imaging of live cells, we show here that an amyloidogenic polyglutamine-containing protein first forms small, amorphous aggregate clusters in the cytosol, chiefly by diffusion. Dynamic interactions among these clusters limited their elongation and led to structures with a branched morphology, differing from the predominantly linear fibrils observed in vitro Some of these clusters then assembled via active transport at the microtubule-organizing center and thereby initiated the formation of perinuclear aggresomes. Although it is widely believed that aggresome formation is entirely governed by active transport along microtubules, here we demonstrate, using a combined approach of advanced imaging and mathematical modeling, that diffusion is the principal mechanism driving aggresome expansion. We found that the increasing surface area of the expanding aggresome increases the rate of accretion caused by diffusion of cytosolic aggregates and that this pathway soon dominates aggresome assembly. Our findings lead to a different view of aggresome formation than that proposed previously. We also show that aggresomes mature over time, becoming more compacted as the structure grows. The presence of large perinuclear aggregates profoundly affects the behavior and health of the cell, and our super-resolution imaging results indicate that aggresome formation and development are governed by highly dynamic processes that could be important for the design of potential therapeutic strategies.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.subjectCell Nucleusen
dc.subjectMicrotubule-Organizing Centeren
dc.subjectAnimalsen
dc.subjectMiceen
dc.subjectPeptidesen
dc.subjectMicroscopy, Fluorescenceen
dc.subjectModels, Biologicalen
dc.subjectFemaleen
dc.subjectMaleen
dc.titleLive-cell super-resolution microscopy reveals a primary role for diffusion in polyglutamine-driven aggresome assembly.en
dc.typeArticle
prism.endingPage268
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameThe Journal of biological chemistryen
prism.startingPage257
prism.volume294en
dc.identifier.doi10.17863/CAM.34478
dcterms.dateAccepted2018-10-29en
rioxxterms.versionofrecord10.1074/jbc.ra118.003500en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-01en
dc.contributor.orcidLu, Meng [0000-0001-9311-2666]
dc.contributor.orcidBanetta, Luca [0000-0003-2055-9584]
dc.contributor.orcidBates, Gillian P [0000-0002-4041-6305]
dc.contributor.orcidZaccone, Alessio [0000-0002-6673-7043]
dc.contributor.orcidKaminski, Gabriele [0000-0002-1843-2202]
dc.contributor.orcidTunnacliffe, Alan [0000-0001-8570-125X]
dc.contributor.orcidKaminski, Clemens [0000-0002-5194-0962]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (089703/Z/09/Z)
pubs.funder-project-idBBSRC (BB/H023917/1)
pubs.funder-project-idEPSRC (EP/H018301/1)
pubs.funder-project-idMRC (MR/K02292X/1)
pubs.funder-project-idMRC (G0902243)
pubs.funder-project-idMRC (MR/K015850/1)
pubs.funder-project-idEPSRC (EP/L015889/1)
pubs.funder-project-idEuropean Research Council (233232)
rioxxterms.freetoread.startdate2019-11-06


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