Chapter 3 80 ABSTRACT Leukodystrophies, once considered solely glial disorders, are increasingly associated with neuronal dysfunction. This study examines neuronal involvement in 4H leukodystrophy and globoid cell leukodystrophy (GLD) using human iPSC-derived neuron–astrocyte co-cultures and neuron mono-cultures. In 4H neuron mono-cultures, neurons had shorter neurites and a progressive decline in mitochondrial transport, opposed time increased mitochondrial transport in control neuron cultures. Additionally, transcriptomic analysis of 4H neurons revealed downregulation of genes related to synaptic signalling and cerebral cortex regionalization and development, and upregulation of genes related to morphogenesis and ribosomal pathways, suggesting potential mechanisms underlying 4H neuron abnormalities. In contrast, GLD neurons lacked distinguishing transcriptomic signatures. Also, in GLD neuron-astrocyte co-cultures no significant differences in neurite outgrowth, microtubule dynamics, or mitochondrial transport were observed, and psychosine accumulation, a hallmark of GLD, was absent. In GLD neuron mono-cultures only moderate psychosine accumulation was detected. This study highlights potential molecular pathways in 4H pathology and emphasizes the limitations of current in vitro models for studying leukodystrophies, providing a foundation for future research.
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