Date of Award

January 2026

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Monika Sharma

Second Advisor

Clemens Scherzer

Abstract

Neurologic disease is the leading cause of disability globally and Parkinson’s disease (PD) has been the fastest growing neurologic brain disease over the last several decades. Despite the immense burden of PD on patients and society, there has yet to be an efficacious disease-modifying therapy. Investigation of candidate pharmaceuticals that have already been approved by the FDA for other conditions might provide an expedited path to the advent of disease-modifying therapy. There is a rich history of drug repurposing for symptomatic therapy for PD, with amantadine as the preeminent example. In order to identify candidate therapeutics for possible repurposing, an especially large drug-wide association study was conducted by Dr. Trond Riise’s group at the University of Bergen, Norway. From the 4.6 million Norwegians in the study population and nearly 650 million prescriptions analyzed, several drug categories were identified as possible candidates, including ezetimibe‒a second-line lipid-lowering agent which blocks hepatic recycling and cholesterol absorption via inhibition of NPC1L1. Another epidemiological study, the Harvard Biomarker Study, also identified ezetimibe as possibly neuroprotective, with lower rates of PD development and progression within the cohort exposed to ezetimibe. Thus, based on these association studies and other preliminary data, we hypothesized that ezetimibe possibly exerts neuroprotective disease-modifying effects in PD through restoration of mitochondrial function and from specifically targeting NPC1L1 or its paralog NPC1. We conducted a series of 2 assays probing mitochondrial function, including the ATP production assay and the mitochondrial superoxide production (MitoSOX) assay, to measure the potential effect of ezetimibe in a cell model of PD. We then conducted immunoblotting to measure the expression levels of the 5 mitochondrial complexes in the presence of ezetimibe versus a vehicle control. Lastly, we further probed for a possible target pathway by performing qPCR, looking at expression levels of RNA for SNCA, NPC1L1, NPC1, and NPC2. The ATP production assay and the MitoSOX assay did not demonstrate a significant effect of ezetimibe on mitochondrial function. Immunoblotting did not show any significant changes in protein expression across all 5 mitochondrial complexes post ezetimibe treatment. Lastly, qPCR demonstrated significant changes in RNA expression in NPC1 with treatment of 10 µM ezetimibe for 48 hours. NPC1 plays a key role in cholesterol trafficking within endosomes and lysosomes. These results suggest that ezetimibe possibly modulates lysosomal pathways, though investigations to directly measure lysosomal function are required to further elucidate the possible disease-modifying effects of ezetimibe.

Comments

This is an Open Access Thesis.

Download
Open Access

This Article is Open Access

Share

COinS