Abstract: Patients with hypomyelinating leukodystrophies (HLDs), multiple sclerosis (MS), and leukodystrophies including Aicardi-Goutières syndrome, adrenoleukodystrophy, Alexander disease, Canavan disease, cerebrotendinous xanthomatosis, Krabbe disease/globoid cell leukodystrophy, metachromatic leukodystrophy, and Niemann-Pick disease have severe demyelination or hypomyelination. Congenital HLDs are a rare group of disorders characterized by a myelin deficit of the brain that is identified by magnetic resonance imaging, and patients with HLDs typically have nystagmus and motor deficits. In most cases, symptoms begin in infancy and include problems with feeding, a whistling sound when breathing, progressive spasticity leading to joint deformities (contractures) that restrict movement, speech difficulties (dysarthria), ataxia, and seizures. The molecular pathogenesis of HLD1 (also known as Pelizaeus-Merzbacher disease) and MS has been analyzed and well characterized using mouse models such as proteolipid protein 1 (PLP1)-overexpressing transgenic mice (PLP1-tg) (Kagawa et al., 1994) and cuprizone-induced demyelination mice (Bacmeister et al., 2020). The molecular pathology of HLD1 is known to involve an overdose of PLP1 protein, which causes the accumulation of unfolded proteins, leading to the endoplasmic reticulum stress, apoptosis of oligodendrocytes, and demyelination (Figure 1A panel a; Torii et al., 2014). An increasing number of studies have reported genetic mutations that cause similar protein misfolding, dysfunction, and/or mislocalization associated with HLDs. However, these molecular pathology of HLDs are largely unknown because most of HLDs mice have still not been generated yet. On the other hand, cuprizone-induced mice were used as MS mice and were easily generated. Thus, cuprizone-induced demyelination mice have been widely used in research into acute and chronic demyelination disorders and have been well characterized for at least 40 years (Figure 1A panel b).