A molecular perspective of Parkinson’s disease: examining the mechanisms driving alpha-synuclein aggregation
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Atieh, Tamr Bassam.
A molecular perspective of Parkinson’s disease: examining the mechanisms driving alpha-synuclein aggregation. Retrieved from
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TitleA molecular perspective of Parkinson’s disease: examining the mechanisms driving alpha-synuclein aggregation
Date Created2022
Other Date2022-01 (degree)
Extent186 pages : illustrations
DescriptionParkinson’s disease (PD) is characterized by protein inclusions that result in neurodegeneration within the substantia nigra. These inclusions, called Lewy bodies, are amyloid fibrils primarily composed of the intrinsically disordered protein α-synuclein (αSyn). Attempts to understand the molecular mechanisms by which αSyn aggregates from a collection of monomeric ensembles into a highly ordered fibrillar structure is of substantial interest to the scientific community. In the present work, we look at the molecular underpinnings that drive αSyn aggregation and make attempts at delaying or inhibiting the fibrillization process. αSyn contains three domains: a slightly positively charged N-terminus, a non-amyloid ß component (NAC), and an acidic C-terminus that all work cooperatively to drive aggregation. Recent research has determined that the NAC is essential to fibrillization propensity. In addition, ß-synuclein (ßSyn), a homologous protein to αSyn, contributes to the delaying of αSyn aggregation which prompted research into understanding αSyn and ßSyn interactions. To establish the importance of each domain within the realm of these synucleins, we created domain swapped chimeras and incubated them with αSyn monomer to see which domains on αSyn or ßSyn are important to the aggregation process. While the NAC component remains the important domain that ensures fibrillization, the N and C termini of ßSyn contribute greatly to delaying αSyn aggregation. Further, in attempts to completely delay the αSyn aggregation process, we focus our attention on the antioxidative protein DJ-1. First described as a protein linked with early onset PD, DJ-1 was shown to inhibit αSyn fibrillization by an unknown mechanism. In this work, we show that the mechanism by which DJ-1 inhibits αSyn aggregation is through binding and scavenging αSyn oligomers thereby preventing further propagation of αSyn aggregation. In addition, the binding site of DJ-1 was determined to be the catalytic triad and that the oxidation state of the critical cysteine residue C106 is imperative for its functionality. DJ-1 is shown to suppress the effects of oxidative stress and acts as a scavenger for reactive oxygen species. Oxidative stress is a known mechanism that enhances the toxicity and aggregation propensity of αSyn, and DJ-1 functionality may stem from combating the effects of oxidation. Another mechanism by which αSyn becomes more neurotoxic is through glycation, the nonenzymatic addition of sugar aldehydes to protein sidechains. Glycation of αSyn alters the biophysical characteristics of the monomer as measured by enhanced backbone dynamics, impairment of fibrillization, and increased oligomer formation. While DJ-1 is hypothesized to be a deglycase, a repair enzyme to the damage caused by glycation, our present work shows that DJ-1 does not chemically deglycate αSyn. Instead, through binding to oligomeric forms of glycated αSyn, this frees up monomers of αSyn and restores monomeric character. This novel interaction may play a role in preventing the propagation of αSyn aggregation and may enhance clearance of the free monomers within the cell. As a consequence of these interactions, we clarify DJ-1’s role in the realm of PD as a chaperone targeting aggregated forms of αSyn, preventing propagation and amyloid formation. Therapeutics that mimic the catalytic site of DJ-1 or through upregulation of DJ-1 expression may be a viable pathway towards alleviating PD pathology caused by αSyn toxicity induced by oxidative stress or glycation.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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