Propagation of Oligomeric α-Synuclein and Amyloid-β: Implications for Parkinson's and Alzheimer's Diseases

<p>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 <strong>α</strong>-synuclein (<strong>α</strong>S) and amyloid-<strong>β </strong>(A<strong>β</strong>) 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 <strong>α</strong>S and A<strong>β </strong>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.</p> <p>In this work, the ability of oligomeric species of <strong>α</strong>S and A<strong>β </strong>to cross-propagate their oligomeric state was investigated. Oligomeric species of <strong>α</strong>S were generated in the presence of dopamine (DA) were characterized. Five discrete and stable dopamine-derived <strong>α</strong>S 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 <strong>α</strong>S monomers. DSOs could also cross-propagate to A<strong>β</strong>42 monomers, yielding A<strong>β</strong>42 oligomers. In addition, A<strong>β</strong>42 oligomers (LFAOs) were shown to be capable of crosspropagating their oligomeric state to <strong>α</strong>S 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.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Masters Thesis

Discipline thesis:degree_discipline

Chemistry and Biochemistry

Year dc:date.available

2014

Author dc:creator

• Planchard, Matthew Stephen

Contributors dc:contributor

• Vijay Rangachari
• Sabine Heinhorst
• Douglas Masterson

• Amyloid
• synuclein
• prion
• propagation
• oligomers
• Parkinson's
• Biochemistry
• Biochemistry, Biophysics, and Structural Biology
• Diseases
• Life Sciences
• Medical Biochemistry
• Medical Sciences
• Medicine and Health Sciences
• Molecular and Cellular Neuroscience
• Nervous System Diseases
• Neuroscience and Neurobiology

Repository record dc:identifier

https://aquila.usm.edu/masters_theses/25

OAI identifier oai:identifier

oai:aquila.usm.edu:masters_theses-1022