Abstract
Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the
N
-acyl chain. Mutations in the
FA2H
gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants,
Fa2h
−/−
mice (
Fa2h
deleted in all cells by germline deletion) and
Fa2h
flox/flox
Cnp1-Cre mice (
Fa2h
deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of
Fa2h
−/−
mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected.
Fa2h
−/−
mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult
Fa2h
−/−
mice. The cerebellar deficits in 12-month-old
Fa2h
flox/flox
Cnp1-Cre mice were indistinguishable from
Fa2h
−/−
mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast,
Fa2h
flox/flox
Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in
Fa2h
−/−
mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.