Date of Award

5-2014

Degree Type

Masters Thesis

Degree Name

Master of Science (MS)

Department

Chemistry and Biochemistry

Committee Chair

Vijay Rangachari

Committee Chair Department

Chemistry and Biochemistry

Committee Member 2

Sabine Heinhorst

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Douglas Masterson

Committee Member 3 Department

Chemistry and Biochemistry

Abstract

The aggregation of amyloidogenic proteins is a critical event in the pathology of a variety of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The proteins α-synuclein (αS) and amyloid-β (Aβ) are involved in the formation of amyloid lesions observed in PD and AD, respectively. Both PD and AD exhibit a significant amount of co-pathology in clinical settings, and the αS and Aβ proteins have been shown to interact in vitro. Recent experimental consensus has shown oligomeric species to be significant, if not primary, sources of toxicity in these diseases.

In this work, the ability of oligomeric species of αS and Aβ to cross-propagate their oligomeric state was investigated. Oligomeric species of αS were generated in the presence of dopamine (DA) were characterized. Five discrete and stable dopamine-derived αS oligomers (DSOs) ranging from 2-14mers were fractionated. All isolated DSOs were formed along an off-fibril formation pathway. Their mechanism of formation was dependent on the oxidation of DA, implicating the quinone form of DA as an inducer of oligomerization. Importantly, DSOs could self-propagate through interactions with αS monomers. DSOs could also cross-propagate to Aβ42 monomers, yielding Aβ42 oligomers. In addition, Aβ42 oligomers (LFAOs) were shown to be capable of crosspropagating their oligomeric state to αS monomers. This work provides the first experimental evidence for the cross-propagation of oligomeric states among neurodegenerative proteins and provides a potential molecular explanation for the copathology causing increased disease severity in many PD and AD patients.