Characterization of alpha-synuclein-induced vesicular accumulation in a yeast model of Parkinson's disease / James H. Soper.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Soper, James H.

Contributor:

Lee, V. M.-Y. (Virginia M.-Y.), advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Neurosciences.

Academic Dissertations as Topic.

Medical Subjects:

Neurosciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

ix, 192 pages : illustrations ; 29 cm

Production:

2008.

Summary:

The presence of alpha-synuclein protein inclusions in the brain is a central pathological hallmark of Parkinson's disease and several other neurodegenerative diseases. alpha-Synuclein is deposited in the form of amyloid fibrils in all of these diseases, and the process by which alpha-synuclein forms these fibrils is thought to be the primary insult that leads to the symptoms of these disorders. Currently, the mechanisms by which these proteinaceous inclusions form, and whether they directly cause disease pathogenesis, are unknown. Therefore, the generation of a model system in which to characterize alpha-synuclein aggregation is of vital importance to researchers attempting to design therapies for these diseases. This thesis examines a yeast model of alpha-synuclein aggregation and clarifies the nature of alpha-synuclein aggregates recently visualized in yeast cells. We demonstrate that asynuclein aggregation in yeast is toxic and is dependent on membrane binding and hydrophobic interactions, and examine the structural determinants of alpha-synuclein that are necessary for these processes. We demonstrate that alpha-synuclein aggregation in yeast disrupts Golgi markers. We report the significant observation that alpha-synuclein aggregates in yeast are not fibrillar inclusions, but are massive accumulations of cytoplasmic vesicles. We demonstrate that these vesicle accumulations specifically sequester Rab GTPase proteins, and that these cells are sensitive to disruption of the endocytic pathway, particularly retrograde endosome-Golgi trafficking. These findings provide important data as to the usefulness of the yeast system as a model of alpha-synuclein aggregation. Furthermore, these findings present the yeast system as a model to study the function of alpha-synuclein, and demonstrate novel findings about the possible relationship between asynuclein function and toxicity. This work furthers our understanding of the cellular role of alpha-synuclein and may provide the basis for new studies into the pathogenic mechanism of alpha-synuclein and the development of possible therapeutic interventions for human disease.

Notes:

Adviser: Virginia M-Y. Lee.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 2008.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3346195