Chapter 1 8 The human brain is an incredibly complex organ, housing billions of interconnected neurons and glial cells that form highly specialized networks. Despite remarkable advancements in neuroscience, many of the brain’s functions and developmental processes remain only partially understood. What is clear, however, is that even minor deviations from normal brain development can lead to profound neurological and cognitive impairments. Among the many disorders that disrupt brain function are leukodystrophies—a diverse group of genetic diseases primarily affecting the brain’s white matter. One of the white matter components often affected is myelin, the insulating sheath that surrounds neuronal axons and facilitates efficient electrical signal transmission. One such leukodystrophy is 4H leukodystrophy, a disease that used to be characterized by hypomyelination along with hypodontia and hypogonadotropic hypogonadism. However, when in 2011 mutations in genes encoding for subunits of RNA polymerase III - a ubiquitous protein essential for cellular transcription - were identified as disease-causing variants, more patients with a wider range of clinical presentations were diagnosed. While the identification of the mutations provided an important first step toward understanding the genetic basis of 4H syndrome, it also raised critical questions about the underlying disease mechanisms and, most importantly, which cells should be the target of future treatments. Current treatments remain supportive, focusing on symptom management rather than addressing the root cause. Identifying which cell types are primarily affected and elucidating the processes disrupted by Pol III mutations are crucial steps toward developing targeted therapies. In this thesis, we aim to bridge this knowledge gap by modelling the cellular phenotypes of 4H leukodystrophy using human induced pluripotent stem cells (hiPSCs) and advanced in vitro systems. These models allow us to explore how Pol III defects affect brain cell development, particularly those involved in myelination and neuronal function. Through these studies, we seek to uncover disease mechanisms, identify vulnerable cell types, and evaluate potential therapeutic targets that could pave the way for future treatments.
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