Date of Award

6-2014

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Education

First Advisor

Omar M.A EI-Agnaf

Second Advisor

Ahmed Al Marzouqi

Third Advisor

Abdu Adem

Abstract

An abundance of genetic, biochemical and histopathological evidence suggests that the formartion of α-synuclein (α-syn) protein deposits is an important, and likely seminal, step in the development of several important neurodegenerative diseases, the so-called synucleinopathies, including Parkinson’s Disease (PD), intensive research, to date, the only accepted diagnosis for PD is based on clinical criteria. α-syn conversion from soluble monomers into oligomers or fibrils represents a crucial step in synucleinopathies pathogenesis; however, the exact mechanism underlying the cellular aggregation has not been fully elucidated. A growing body of evidence suggests that α-syn soluble oligomers, rather than mature fibrils, are the neurotoxic species. A lack of biomarkers for the early diagnosis of PD is a major obstacle to providing early disease-modifying therapies. Toward this aim, we developed and thoroughly characterized novel confirmation-specific monoclonal antibodies that specifically recognize α-syn pathology. Importantly, our antibodies were able to detect different assemblies of α-syn aggregates, ranging from soluble oligomers to mature insoluble fibrils. Considering the critical pathogenic role of α-syn soluble aggregates, our novel antibodies might provide important diagnostic and therapeutic opportunities.

Next, we developed new immunoassays to quantify different species of α-syn (total α-syn, α-syn oligomers and p-S129- α-syn) levels in cerebrospinal fluid (CSF) from PD patients and age-matched healthy controls. Combining the measurements of different α-syn species in CSF, we found a clear differential CSF pattern between PD and controls. Our results validated the usefulness of combining multiple CSF biomarkers in improving PD diagnostic accuracy and prognostic evaluation.

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