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dc.contributor.authorTrubetskov, Mikhail
dc.date.accessioned2018-04-11T03:48:44Z
dc.date.available2018-04-11T03:48:44Z
dc.date.issued2017en_US
dc.identifier.urihttp://hdl.handle.net/11343/210453
dc.description© 2017 Dr. Mikhail Trubetskov
dc.description.abstractFormation of microscopically visible intracellular aggregates (inclusions) containing exon 1 fragments of mutant Huntingtin (mHttex1) is a hallmark of Huntington’s Disease (HD) pathology. The role of inclusions in HD pathogenesis is not fully understood and is described by two alternative models. One model considers Huntingtin inclusions being adaptive by sequestering toxic soluble mHttex1 and prolonging cellular survival. In the other, inclusions are toxic by coaggregating with growth factors and proteins crucial for normal cellular activity. Through a fortuitous discovery of early-formed and mature types of mHttex1 inclusions by applying a genetically-encoded biosensor of mHttex1 conformation, we describe a mechanism that ties these two models together. Cells with soluble mHttex1 lived for a shorter period than the ones with inclusions and exclusively died via apoptosis. Early-formed inclusions contained ribonucleoproteins, mRNA splicing and processing machinery. As aggregation progressed, chaperones and aggregation-prone proteins were recruited into mature inclusions that converted into amyloid state. Cells with mature inclusions became metabolically inactive and died exclusively via necrosis. Our data suggests inclusions arise via mHttex1 halting protein translation. Soluble mHttex1 appears to be the trigger for apoptosis in the system. Inclusion formation sequesters soluble mHttex1 and correlates with a reduced risk of apoptosis. The prolonged survival of cells with inclusions correlates with progressive metabolic dysfunction, a failed attempt to clear inclusions and ultimate switch from apoptosis to necrosis.en_US
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dc.subjectapoptosisen_US
dc.subjecthuntingtinen_US
dc.subjectcell deathen_US
dc.subjectlive cell imagingen_US
dc.subjectaggregationen_US
dc.subjectneurodegenerationen_US
dc.subjectHuntington's Diseaseen_US
dc.titleMechanisms of inclusion assembly in Huntington’s diseaseen_US
dc.typePhD thesisen_US
melbourne.affiliation.departmentBio21
melbourne.affiliation.facultyAffiliates
melbourne.thesis.supervisornameDanny Hatters
melbourne.contributor.authorTrubetskov, Mikhail
melbourne.accessrightsOpen Access


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