Abstract

This thesis investigated the role of lipid peroxidation in Niemann-Pick type C (NPC) disease, a rare lysosomal storage disorder characterized by significant neurodegeneration, with a focus on its relationship to cholesterol accumulation and regional brain susceptibility to neurodegeneration. I hypothesized that cholesterol accumulation could lead to lipid peroxidation through non-enzymatic processes, independent of cell death or inflammation. In vitro experiments demonstrated higher levels of cholesterol accumulation and lipid peroxidation in NPC cells. Transcriptomic analysis of NPC mouse brains revealed significant upregulation of lipid peroxidation-related pathways in the more susceptible cerebellum compared to the cerebral cortex. Lipidomic analysis revealed higher baseline levels of cholesterol and cardiolipin in the cerebellum, which may explain its increased susceptibility to lipid peroxidation. We utilized a double knockout mouse model (Npc1-/- | Cyp27a1-/- ) to study NPC. In this model, the Npc1-/- mutation represents the disease, while the Cyp27a1-/- mutation disrupts the conversion of cholesterol to 27-hydroxycholesterol, a pro-inflammatory molecule that can cross the blood-brain barrier. Our observations indicated that increased cholesterol accumulation resulted in higher levels of malondialdehyde (MDA), a byproduct of lipid peroxidation. This finding suggests that lipid peroxidation in NPC is likely due to the peroxidation of unsaturated fatty acids, particularly cardiolipin in the mitochondria. These findings suggest that the pattern of

neurodegeneration in NPC may be associated with the increased presence of cardiolipin in the cerebellum. Single therapies targeting either inflammation or oxidative stress were ineffective in significantly prolonging lifespan in NPC mice, highlighting the complex pathophysiology of the disease and the need for combination therapies. This research not only contributes to our understanding of the mechanisms of lipid peroxidation in NPC but also provides insights into the role of lipid dysregulation in other neurodegenerative diseases and emphasizes the importance of targeting multiple pathways for effective treatment strategies.

LLU Discipline

Neuroscience, Systems Biology, and Bioengineering

Department

Neuroscience

School

School of Medicine

First Advisor

Christopher G. Wilson

Second Advisor

Salvador Soriano Castell

Third Advisor

Antonio Currais

Fourth Advisor

Alfonso Duran

Fifth Advisor

Johnny D. Figueroa

Sixth Advisor

Michael J. Pecaut

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2026

Date (Title Page)

8-2026

Language

English

Library of Congress/MESH Subject Headings

Niemann-Pick disease Type C; Lipid peroxidation; Neurodegeneration; Oxidative stress

Type

Dissertation

Page Count

xxvii, 203 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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