Abstract
Pelizaeus–Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood–brain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not lead to a major advancement of hypomyelination, potentially because the intact blood–brain barrier precludes its entry into the CNS. We therefore turned to a PMD mouse model with preserved blood–brain barrier integrity and show that a high-fat/low-carbohydrate ketogenic diet restored oligodendrocyte integrity and increased CNS myelination. This dietary intervention also ameliorated axonal degeneration and normalized motor functions. Moreover, in a paradigm of adult remyelination, ketogenic diet facilitated repair and attenuated axon damage. We suggest that a therapy with lipids such as ketone bodies, that readily enter the brain, can circumvent the requirement of a disrupted blood–brain barrier in the treatment of myelin disease.
Highlights
Primary defects in lipid metabolism are associated with myelin disease [13] and vice versa, a growing number of neurodegenerative diseases [1, 2, 14, 68], including the hereditary leukodystrophy Pelizaeus–Merzbacher disease (PMD), is associated with a perturbed brain lipid metabolism [29, 57, 63, 73]
We found that the blood–brain barrier (BBB) is perturbed in a line of Plp1 transgenic mice (Plp1tg-72 [51]), a model of PMD, allowing the entry of cholesterol from the circulation into the CNS
In an individual, compassionate use trial, we first asked whether we could translate the dietary treatment approach in two patients with PMD caused by PLP1 duplication
Summary
Primary defects in lipid metabolism are associated with myelin disease [13] and vice versa, a growing number of neurodegenerative diseases [1, 2, 14, 68], including the hereditary leukodystrophy Pelizaeus–Merzbacher disease (PMD), is associated with a perturbed brain lipid metabolism [29, 57, 63, 73]. Axon degeneration is a feature of the PMD pathology, leading to cortical atrophy that likely contributes to neurological impairment [9, 35] It has been shown in vitro and in vivo that lipid supplementation can enhance myelination in hypomyelinating pathologies and thereby promote repair [6, 21, 55,56,57]. We found that the BBB is perturbed in a line of Plp transgenic mice (Plp1tg-72 [51]), a model of PMD, allowing the entry of cholesterol from the circulation into the CNS. This study combines two important therapeutic targets, cholesterol for the support of remyelinating oligodendrocytes and ketone bodies for the metabolic support of the axonal compartment
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