Introduction 17 1 brain cell types which are known to be involved in different genetic white matter disorders. The following sections provides a brief introduction to the cell lineages we aimed to investigate, and their known involvements in genetic white matter disorders. Oligodendrocytes The primary cells responsible for myelination are oligodendrocytes, which originate from NG2-expressing cells known as polydendrocytes or oligodendrocyte precursor cells (OPCs). Mature oligodendrocytes extend multiple protrusions that wrap around axons, forming a lipid-dense myelin sheath. This sheath enhances electrical signal conduction while also providing metabolic support, regulating ion and water homeostasis, and adapting to activity-dependent neuronal signals (Kuhn et al., 2019). Within genetic white matter disorders, some have primary myelin pathology, and hence are classified as myelin disorders (van der Knaap & Bugiani, 2017). Within these myelin disorders, three subcategories can be distinguished based on the type of myelin pathology: hypomyelination, demyelination and myelin vacuolization. An example of a hypomyelinating white matter disorder is Pelizaeus-Merzbachter disease, which is caused by variants in PLP1, a gene that is mainly expressed in mature oligodendrocytes (Torii et al., 2014). Metachromatic leukodystrophy (MLD) and Globoid cell leukodystrophy (GLD) also known as Krabbe disease and the cerebral form of X-linked Adrenoleukodystrophy are characterized by demyelination. Those disease are respectively caused by variants in ASA, GALC and ABCD1 and cause pathological accumulation of respectively sulfatides and psychosine due to lysosomal storage disorders and very long chain fatty acids due to peroxisomal dysfunction (Abed Rabbo et al., 2021; Berger et al., 2014). The last category is characterized by myelin vacuolization and among this falls the leukodystrophy Canavan disease. Canavan disease is caused by ASPA variants a gene that codes for the substrate enzyme aspartoacylase, which hydrolyzes N-acetylaspartic acid (NAA) to acetate and aspartate (Hoshino & Kubota, 2014). Neurons Since oligodendrocytes myelinate neuronal axons, neurons are crucial in the mimicking of (hypo)myelination. Neurons transmit information through voltage discharges along their cell membranes. Depending on the neurotransmitters they release at the synapse, neurons are broadly divided into excitatory/glutamatergic or inhibitory/GABAergic subtypes. Certain neuronal subtypes, such as inhibitory parvalbumin-expressing neurons, are particularly likely to be myelinated (Stedehouder et al., 2017). A subclass of genetic white matter
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