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Mass Spectrometry Imaging, Lipidomics, and Proteomics Studies in Neurodegenerative Diseases

thesis
posted on 2023-05-01, 00:00 authored by Koralege Praneeth Chandimal Pathmasiri
Mass spectrometry (MS) is a powerful analytical technique that can be used to identify and quantify unknown molecules in a complex sample. In biological systems, MS analysis can be performed on biomolecules such as proteins, nucleic acids, lipids, and other metabolites. MS analysis of these biomolecules in animal tissues and cells is crucial, specially to identify the changes that take place due to disease conditions. This knowledge can be used to understand disease mechanisms, discover biomarkers, and invent targets for drug development. In this dissertation, mass spectrometry was used to study two neurodegenerative diseases, Niemann-pick type C1 (NPC1) and Krabbe disease. Mass spectrometry imaging was performed on the brain tissue of NPC1-null mouse model to identify quantitative and spatial changes in lipids due to the disease. Findings were further investigated using LC-MS and revealed alteration of highly bioactive phosphoinositide lipids in the mutant mice brain myelin. The impact of the NPC disease on the brain myelin was further studied using mass spectrometry proteomics. Multiple proteins related to ATP synthesis, ion transport, and myelination were found to be altered in the mutant brain myelin. Moreover, this study revealed that ATP production in human oligodendrocyte cells is decreased upon the inhibition of NPC1 protein. In addition, a workflow was developed to purify the NPC1 protein and perform hydrogen-deuterium exchange mass spectrometry. This workflow can be used to study the lipid-binding sites of the NPC1 protein. Finally, mass spectrometry lipidomics was used to investigate the brain lipidome of Krabbe disease in a mouse model, which identified potential biomarkers and revealed alterations in the sphingolipid metabolism pathway.

History

Advisor

Cologna, Stephanie M

Chair

Cologna, Stephanie M

Department

Chemistry

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Hanley, Luke Yang, Xiaojing Gao, Rui Sanchez, Laura

Submitted date

May 2023

Thesis type

application/pdf

Language

  • en

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