{"doi":"10.7302/8224","title":"Mechanisms of Dysmyelination in Niemann-Pick Type C Disease","abstract":"Lysosomal storage diseases (LSDs) are a group of over 70 inherited disorders that result in lysosomal dysfunction and accumulation of substrates. This lysosomal impairment leads to a variety of secondary effects within the cell including impaired autophagy, metabolic dysregulation, defective calcium homeostasis, oxidative stress, and activation of cell death pathways. The clinical presentation of LSDs is heterogeneous, but two-thirds of LSDs cause neurological symptoms. One example of this is Niemann-Pick Disease type C, an autosomal recessive LSD that arises predominantly in children. Niemann-Pick type C is caused by mutations in either of two proteins, NPC1 or NPC2. These proteins work together in the lysosomal compartment to efflux cholesterol from the lysosome to be used in various cellular processes, and mutation in these proteins leads to the accumulation of unesterified cholesterol in late endosomes and lysosomes. The result is a progressive neurodegeneration and early death. While there is increased understanding of the functions of NPC1 and NPC2 at the lysosome, the mechanisms that contribute to the neurodegeneration seen in Niemann-Pick type C remain poorly understood. As such, there are currently no FDA-approved therapeutics to treat the disease. This thesis aims to understand the contribution of neuron-glial interactions to neurodegeneration in Niemann-Pick type C with the hope of identifying novel targets for therapeutic intervention. In Chapter 1, this thesis discusses LSDs with a focus on the pathobiology of Niemann-Pick type C. It goes on to discuss the process of oligodendrocyte formation and myelination, how this process is regulated, and how impairments in myelination can contribute to neurological disease. Chapter 2 demonstrates that oligodendrocytes are among the earliest cell types effected in Niemann-Pick type C. It shows that cholesterol homeostasis is vital to the epigenetic regulation within and the differentiation of oligodendrocyte lineage cells. Chapter 3 explores how the disease progresses, comparing transcriptional changes and affected cell types in presymptomatic brains to brains acquired after symptom onset. It also compares transcriptional changes in the brain to those in another impacted organ, the liver, to detect altered pathways that may be ubiquitous across tissues. Finally, Chapter 4 summarizes the data presented and discusses remaining questions and future directions. This work seeks to shed light on the mechanisms that cause neurodegeneration in Niemann-Pick type C, and to provide a transcriptional database for the field to use as a tool to better understand the disease. My hope is that this work will contribute to the identification of new therapeutic targets.","journal":"Deep Blue (University of Michigan)","year":2023,"id":415934,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":662022,"name":"Thaddeus J. Kunkel","orcid":"0000-0002-9458-6000","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:22:15.958504Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}