Substrate Selection by the 20S Proteasome and Implications in Disease Pathogenesis

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dc.contributor.advisorThomas, Philip J.en
dc.creatorRitchie, Caroline Marieen
dc.date.accessioned2013-01-16T21:16:54Z
dc.date.issued2013-01-16
dc.description.abstractAlpha-synuclein is a major component of Lewy bodies, large insoluble protein aggregates, found in various regions of the brain in patients with Parkinson’s disease, diffuse Lewy body disease, and the Lewy body variant of Alzheimer’s disease. Within Lewy bodies, several modifications of alpha-synuclein have been identified, including truncations from either terminus. Several observations support a role for C-terminally truncated forms of alpha-synuclein in disease pathogenesis. While multiple proteases have been implicated in the metabolism of alpha-synuclein, C-terminally truncated forms of alpha-synuclein produced by the 20S proteasome in vitro, through a ubiquitin-independent mechanism, are similar to those found in the cingulate cortex of patients with Lewy body diseases. The work presented here describes an investigation into the mechanism by which alpha-synuclein is recognized and degraded by the 20S proteasome, aimed at the properties of both the substrate and the enzyme required for activity. The results shown reveal a previously unappreciated mechanism by which the 20S proteasome selects its substrates, and this activity is coupled to gate opening in mammalian proteasomes. Additionally, a post-translational modification of the 20S proteasome was identified that correlates with activity of the enzyme against alpha-synuclein.en
dc.identifier.oclc828677280
dc.identifier.urihttps://hdl.handle.net/2152.5/1222
dc.language.isoenen
dc.subjectAlzheimer Diseaseen
dc.subjectLewy Bodiesen
dc.subjectalpha-Synucleinen
dc.titleSubstrate Selection by the 20S Proteasome and Implications in Disease Pathogenesisen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2014-12-21
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineMolecular Biophysicsen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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