Abstract

Niemann–Pick Disease Type C (NPC) is a hereditary neurodegenerative disease characterized by selective cell vulnerability, particularly affecting cerebellar anterior Purkinje neurons. These neurons exhibit a distinctive pattern of degeneration due to the loss of NPC1 and/or NPC2 protein function, progressively extending towards posterior cerebellar regions. Historically, research has described NPC as a disorder of intracellular cholesterol handling; however, cholesterol-lowering therapies have not effectively prevented neurological deterioration, and the mechanisms underlying selective neuronal vulnerability remain unclear. Ferroptosis, previously referred to as oxytosis, is a regulated form of cell death driver by iron-induced lipid peroxidation. It has been implicated in several neurodegenerative diseases, and its inhibition has shown therapeutic promise. Based on NPC cellular pathology, it is possible that these features represent interrelated processes of oxytosis/ferroptosis, a mechanism that has yet to be explored in the NPC brain. As such, I hypothesize that loss of NPC1 function increases vulnerability to oxytosis/ferroptosis and that anti-oxytotic/ferroptotic compounds will reverse NPC cellular pathology. Through bioinformatic analyses of pre-symptomatic Npc1─/─ mice and in vitro studies using primary dermal fibroblasts derived from NPC patients, the following evidence suggests that oxytosis/ferroptosis contributes to NPC pathogenesis. These findings highlight the potential of anti-oxytotic/ferroptotic compounds as a promising therapeutic strategy to mitigate neurodegeneration in NPC and other related disorders.

LLU Discipline

Neuroscience, Systems Biology, and Bioengineering

Department

Basic Sciences

School

School of Medicine

First Advisor

William Pearce

Second Advisor

Pamela Maher

Third Advisor

Salvador Soriano

Fourth Advisor

Julia Unternaehrer

Fifth Advisor

Christopher G. Wilson

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2026

Date (Title Page)

3-2026

Language

English

Library of Congress/MESH Subject Headings

Niemann-Pick diseases--Pathophysiology; Ferroptosis; Neurodegenerative diseases--Molecular aspects; Biochemical markers; Amyloid precursor protein

Type

Dissertation

Page Count

xvi, 157 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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