The leukodystrophies are a group of disorders that affect myelin. Most of the leukodystrophies are hereditary and cause progressive degeneration of the white matter. Currently, there are no cures for any of the leukodystrophies. The focus of this project is a recently identified leukodystrophy caused by mutations in the fatty acid 2-hydroxylase (FA2H) gene, which result in lack of a type of myelin lipids. Because this disease is caused by a lipid deficiency, there is a distinct possibility that it could be treatable by replacing the missing lipids. The ultimate goal of this study is to develop synthetic lipid therapeutics that can rectify the deficit in patients'myelin lipids, thereby preventing degeneration of the white matter. This project is a preclinical study aimed at developing potential lipid therapeutics using a Fa2h knockout mouse model. FA2H is a lipid biosynthetic enzyme responsible for the synthesis of major myelin sphingolipids. Galactose-containing sphingolipids (galactolipids) make up approximately 30% of total myelin lipids. More than half of the myelin galactolipids contain 2-hydroxy fatty acids (hFA) as their N-acyl chains (hFA-galactolipids). FA2H is the enzyme responsible for the synthesis of the precursor hFA in myelin-forming cells. FA2H deficiency results in loss of hFA in myelin galactolipids, which eventually leads to degeneration of the white matter. There is a possibility that the disabling leukodystrophy could be prevented if myelin-forming cells are exogenously provided with sufficient hFA. To explore this possibility, synthetic hFA-lipids will be administered to Fa2h- knockout mice through the diet. The experiments are designed to address the following three questions: 1) Are the hFA-lipids absorbed? 2) Are the exogenous hFA incorporated into myelin galactolipids? 3) Does long-term administration of the hFA-lipids cause any adverse effects? The study will be conducted in three phases. In the initial phase, Fa2h+/+ and Fa2h-/- weanlings will be fed milled chow supplemented with various synthetic triacylglycerols containing hFA (hFA-TAG) for 5 days to determine whether the test lipid can be absorbed. Blood samples will be collected to determine plasma hFA levels. Those hFA-TAG that are absorbed will be tested for delivery of hFA to myelin. In this phase of the study, Fa2h+/+ and Fa2h-/- weanlings will be fed milled chow supplemented with the hFA-TAG for 4 weeks. At the end of the 4-week period, brain lipids will be analyzed to determine the presence of hFA-galactolipids. Positive compounds will then be tested for long-term effects. If successful, this study will lead to development of potential therapeutics that will prevent and cure the leukodystrophy caused by FA2H deficiency.
Children with FA2H deficiency suffer from a devastating leukodystrophy. Fortunately, the cause of disease has recently been identified: the patients lack a type of fatty acids that make up myelin sheath. The goal of this project is to develop therapeutics to provide the missing fatty acids to patients'myelin to prevent and cure the disease.
