Olivares, Eileen Jacqueline
Eileen is in the Biochemistry, Molecular and Structural Biology Graduate Program, and joined the CMB Training Program in 2022.
Mentor: Dr. Joseph Loo
Amyloid protein aggregates are a hallmark of several neurodegenerative diseases (ND), including, but not limited to, Alzheimer’s disease (AD), Parkinson’s Disease (PD), Huntington’s disease (HD), etc. Fibrils and oligomers, which form aggregates characterized by the presence of β-sheet structures, are thought to contribute to cellular pathology and the degeneration of various brain regions and, hence, are linked to the progression of ND. Even though cytotoxicity was originally attributed to fibrils, evidence points to oligomers being the primary cytotoxic species that result in the progression of ND. The mechanism by which oligomers elicit their toxicity in cells is not entirely clear. To understand this mechanism, it is important to first characterize oligomers. However, their dynamic, polymorphic, and transient nature has made them difficult to isolate and study.
Native mass spectrometry (nMS) is well suited for studying oligomers as it has been found to provide accurate molecular weight and stoichiometric information for various protein complexes, including oligomers. nMS is a soft ionization technique that allows one to study proteins in near-physiological conditions while, in the case of oligomers, keeping non-covalent interface interactions intact. Native top-down mass spectrometry (nTD-MS), where covalent bonds of native proteins are cleaved into fragments, can uncover structural information on amyloid protein oligomers, including the location of the aggregation interface. Elucidating size information and the location of the aggregation interface for these different oligomers may allow us to uncover more about the mechanism by which oligomers induce toxicity and could allow for the characterization of potential therapeutics. Given this, the goals of my research are to 1) optimize nMS to determine the size of various amyloid protein oligomers (e.g., tau, amyloid beta, and ⍺-synuclein), 2) utilize nTD-MS to reveal the location of amyloid protein oligomer interfaces and 3) utilize nMS and nTD-MS to identify how therapeutic compounds change the nature of these oligomeric species. In summary, I hope to characterize amyloid protein oligomers, thus providing information important for understanding how these species contribute to the progression of neurodegenerative diseases.
