Dopamine Induced Post-Translational Modifications of α-Synuclein and the Role of Arsenic in the Development of Parkinson's Disease and Other Synucleinopathies
AuthorCholanians, Aram B.
Pharmacology & Toxicology
AdvisorMonks, Terrence J.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
EmbargoRelease after 01-Jan-2017
AbstractSynucleinopathies are a family of neurodegenerative diseases, with the distinctive pathological feature of Lewy bodies, which include Parkinson’s disease. Lewy bodies are intracellular inclusions filled with α-synuclein, a small neuronal protein with prion-like properties. The main function of α-synuclein is not fully understood, however, it plays a major role in disease progression. Dopamine interactions with α-synuclein have also been implicated in the progression of Parkinson’s disease. Dopamine crosslinks α-synuclein and causes generation of toxic oligomeric species of the protein. Little is known about dopamine-α-synuclein adducts, and one section of the current dissertation focuses on dopamine, levodopa, and α-synuclein interactions. Studies detailed herein demonstrated that lysine residues on α-synuclein have an essential role in the dopamine-induced oligomer formation. Evidence is also presented showing that removal of one of the reactive sites on dopamine by N-acetylcysteine and/or glutathione inhibits dopamine-induced oligomer formation, although the dopamine thiol-conjugates still bind to α-synuclein. In contrast, thiol-conjugates of the dopamine precursor levodopa, significantly increase α-synuclein oligomer formation. The data demonstrate the importance of the scavenging of dopamine and levodopa quinones by N-acetylcysteine and glutathione, and the subsequent changes in the interaction with α-synuclein and its oligomeric states. Environmental factors are key players in the development of synucleinopathies. Although arsenic pesticide exposure has been linked to elevated risk of Parkinson’s disease, there is a paucity of information on arsenic-induced pathological changes, which may be attributed to the onset of neurodegenerative processes. SH-SY5Y cells exposed to environmentally relevant levels of arsenic for 72 hours, develop α-synuclein oligomers and exhibitaugmented expression of stress markers. Thus, there is an increase in autophagy markers and other stress markers, including the accumulation and co-localization of LC3, major autophagy marker, and α-synuclein. Animals transiently exposed to arsenic through drinking water for 2 or 5 weeks, exhibited pathological features resembling synucleinopathies. Although animals were exposed at two-months of age and remained exposure free up to geriatric age (18 months), they still exhibited accumulation of α-synuclein and elevations in autophagy markers. The results demonstrated how even a short period of exposure to a toxicant can have detrimental neurological effects, which may contribute to the development of neurodegenerative disease years after exposure.
Degree ProgramGraduate College
Pharmacology & Toxicology