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Max-Planck-Institut für Experimentelle Medizin
Cholesterol in the pathology of neurodegenerative disorders

In many neurodegenerative diseases the lipid homeostasis in affected. We studied the role of cholesterol in the pathology of Pelizaeus-Merzbacher disease (PMD). PMD is a leukodystrophy without therapeutic options. In most cases of the classical form of PMD, the increase in PLP1 gene dosage is responsible for the disorder. Symptoms develop during the first months of age.

Fig. 1: Working model depicting the most likely influence of cholesterol and PLP on PMD pathology. In WT oligodendrocytes, PLP binds cholesterol at a certain ratio that is required for myelin assembly. In untreated PMD oligodendrocytes, overexpressed PLP leads to the intracellular enrichment of cholesterol. In the cytoplasm, elevated cholesterol impairs intracellular trafficking. Consequently, the cholesterol content in the plasma membrane is reduced, which diminishes myelin assembly. Elevated cholesterol in the ER downregulates cholesterol synthesis. In treated PMD mice, the extra cholesterol improves the ratio of PLP to cholesterol in the plasma membrane (1) and promotes the assembly of myelin membranes (2). This reduces the intracellular cholesterol concentration (3), which in turn induces cholesterol synthesis (4).

In a mouse model for classical PMD we found that oligodendroglial cholesterol homeostasis was affected. As a consequence, the transport of PLP, the major myelin protein of the CNS, to the plasma membrane and secondarily to the myelin sheath was blocked (Fig. 1). This led to the accumulation of PLP and cholesterol intracellularly. In PMD mice, myelin degenerates and oligodendrocytes are lost in the course of the disease.
In treatment trials, we put PMD mice on a high-cholesterol diet. Disease expression was reduced and myelination strongly improved. Taken together, dietary cholesterol can ameliorate pathology in a mouse model of PMD.

Fig. 2: Myelination in the optic nerve strongly improves in PMD mice that received a cholesterol-enriched diet.

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