Role for Lipids in the Cellular Transmission of α-Synuclein

dc.contributor.advisorMichaely, Peter A.en
dc.contributor.committeeMemberThomas, Philip J.en
dc.contributor.committeeMemberDeBose-Boyd, Russell A.en
dc.contributor.committeeMemberAlbanesi, Joseph P.en
dc.creatorPeres, Yairen
dc.date.accessioned2017-09-05T14:50:53Z
dc.date.available2017-09-05T14:50:53Z
dc.date.created2015-08
dc.date.issued2015-07-30
dc.date.submittedAugust 2015
dc.date.updated2017-09-05T14:43:49Z
dc.description.abstractThe presynaptic protein α-Synuclein (α-Syn) abnormally aggregates in the brains of Parkinson's Disease patients. Evidence suggest a transcellular transfer of an oligomeric form of the protein (seed) in a prion-like fashion. The mechanism underlying cell entry is unclear, but studies have implicated the cell surface glycan HSPG followed by macropinocytosis, as a possible uptake route. Secretion and uptake of aggregated α-Syn was reported to be associated with lipid vesicles in cells. Monomeric α-Syn was found to tubulate membranes in-vitro. This work aims to study the significance of membrane association and tubulation by α-Syn to its effect on uptake by cells. Uptake of lipid-associated α-Syn seeds was significantly more efficient than lipid-free uptake. Furthermore, seeds in the presence of monomers and lipids, which formed tubules in-vitro, were more readily internalized than seeds and lipids in the absence of monomers. Lipid associated α-Syn was internalized by cells in an HSPG dependent manner as evident from competitive inhibition and enzymatic digestion experiments. Tubule associated seeds may constitute an efficient mechanism of pathological propagation of synucleinopathies. This mechanism should be considered in any therapeutic approach targeting the inhibition of α-Syn intercellular transfer.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1002857193
dc.identifier.urihttps://hdl.handle.net/2152.5/4205
dc.language.isoenen
dc.subjectalpha-Synucleinen
dc.subjectBrainen
dc.subjectLipid Metabolismen
dc.subjectParkinson Diseaseen
dc.titleRole for Lipids in the Cellular Transmission of α-Synucleinen
dc.title.alternativeRole for lipids in the cellular transmission of [alpha]-Synucleinen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen
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