Dissertation

Combining Molecular Biology and Data Science for Detection and Progression Analysis of Neurodegenerative Diseases

Li, Manci

2024

Overview

Neurodegenerative diseases (NDDs), often characterized by misfolded proteins presenting in the brain, constitute a significant challenge to global health, affecting millions of lives worldwide. Despite the substantial strain these conditions exert on healthcare systems within human populations and the influence they extend on sectors such as agriculture and hunting heritage, effective management strategies have yet to be established. The advent of cutting-edge technologies in molecular biology, especially seed amplification assays (SAAs) for the ultrasensitive detection of misfolded proteins and single-cell sequencing methods for unparalleled resolution of neuronal heterogeneity, offer new avenues for research and hold great potential for enhancing our comprehension of NDDs. The overarching goal of this dissertation is to enhance our knowledge of NDDs by combining methods employed in molecular biology and data science. The first study reports on the identification of Chronic Wasting Disease (CWD) prion seeding activity in white-tailed deer muscle tissues via real-time quaking-induced conversion (RT-QuIC) assays and posits RT-QuIC and similar SAAs as viable tools for monitoring CWD prion spread in both animal and human food supplies. The objective of the second study is to characterize the altered expression of neuropeptides and their cognate receptors in the brain of Alzheimer’s Disease (AD) patients at the single-cell level. The result of this study highlights the potential of neuropeptide-based management strategies for AD and brings forth the hypothesis that neuropeptide production contributes to selective neuronal vulnerability and early pathogenesis in AD. The third study leverages an extensive dataset of spatiotemporal and multiscale transcriptome from 1,890 human brain samples to test the hypothesis at three distinct levels— cellular mechanisms, progression continuum of AD (time), and regional vulnerabilities (space), providing a comprehensive analysis of the alterations of neuropeptide expression across multiple dimensions of the disease. Based on the findings, this dissertation also synthesizes the final hypothesis, coined neuropeptide-mediated probabilistic vulnerability hypothesis for tau-related neurodegenerative diseases, that provides a unifying mechanistic connection across diverse etiologies and subtypes of NDDs involving tau misfolding. Collectively, this dissertation establishes a foundation for future studies aimed at exploring the intricate mechanisms at the core of NDDs and approaches for their diagnosis, prevention, and treatment.

• Publisher: ProQuest Dissertations & Theses
• Subject: Bioinformatics / Cellular biology / Molecular biology / Neurosciences
• ISBN: 9798302131317