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dc.contributor.authorMorgan, Sophie
dc.date.accessioned2018-06-27T12:13:55Z
dc.date.available2018-06-27T12:13:55Z
dc.date.issued2018-01-22
dc.date.submitted2017-10-02
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/277553
dc.description.abstractThe pathological hallmark of many age-related neurodegenerative diseases is the presence of proteinaceous inclusions in nerve cells and glial cells. Alpha-synuclein is the main component of the inclusions of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, as well as of rarer diseases, collectively called synucleinopathies. For a long time, it was widely believed that neurodegenerative diseases were cell-autonomous; however, a more recent hypothesis has suggested that some misfolded proteins resemble prions. Thus, aggregated alpha-synuclein shares features of PrPSc, the scrapie form of the prion protein. The aim of this thesis was to further characterize the prion-like properties of aggregated alpha-synuclein by studying the pathways of seeded aggregation, and to identify the species of alpha-synuclein responsible. I present evidence, using a HEK 293T cell model, that filamentous protein was the most seed-potent form of alpha-synuclein. Recombinant aggregated protein, aggregated alpha-synuclein from mice transgenic for A53T alpha-synuclein, as well as alpha-synuclein aggregates from Parkinson’s disease and multiple system atrophy brains, seeded aggregation. The mechanisms of alpha-synuclein internalization and intracellular trafficking, and how these processes affect seeded aggregation, are not fully understood. I showed that internalization of alpha-synuclein aggregates occurs through clathrin- and dynamin-independent, Cdc42-, actin- and PI3K-dependent endocytosis. Alpha-synuclein aggregates are trafficked to the endolysosomal pathway; a small fraction of lysosomes ruptures, which induces aggregation of expressed cytoplasmic alpha-synuclein, and disruption of autophagy, which in turn enhances seeded aggregation. These findings expand knowledge of the prion-like properties of assembled alpha-synuclein and identify novel mechanisms with therapeutic potential.
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectalpha-synuclein
dc.subjectPrion-like
dc.subjectNeurodegenerative disease
dc.subjectseeded aggregation
dc.titleThe prion-like properties of assembled human alpha-synuclein
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentMRC Laboratory of Molecular Biology
dc.date.updated2018-06-27T11:54:52Z
dc.identifier.doi10.17863/CAM.24868
dc.contributor.orcidMorgan, Sophie [0000-0002-5542-4324]
dc.publisher.collegeDarwin College
dc.type.qualificationtitleDoctor of Philosophy in Molecular Biology
cam.supervisorGoedert, Michel
cam.thesis.fundingfalse
rioxxterms.freetoread.startdate2019-06-27


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