title: Central nervous system dysfunction in a mouse model of FA2H deficiency.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Potter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kern
authors.forename: George
authors.initials: G
authors.lastname: Fullbright
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.forename: Sabrina W
authors.initials: SW
authors.lastname: Yum
authors.forename: Jian J
authors.initials: JJ
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Cheng
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Jagadish Kummetha
authors.initials: JK
authors.lastname: Venkata
authors.forename: P Akbar Ali
authors.initials: PA
authors.lastname: Khan
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hama
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency*; D000818:Animals; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D002493:Central Nervous System Diseases / Q000209:etiology* / Q000235:genetics; D002855:Chromatography, Thin Layer / Q000379:methods; D003711:Demyelinating Diseases / Q000150:complications* / Q000235:genetics*; D004195:Disease Models, Animal; D004576:Electromyography / Q000379:methods; D007859:Learning Disabilities / Q000209:etiology / Q000235:genetics; D008055:Lipids / Q000032:analysis; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000235:genetics; D009431:Neural Conduction / Q000502:physiology; D009900:Optic Nerve / Q000473:pathology / Q000648:ultrastructure; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D053719:Tandem Mass Spectrometry / Q000379:methods; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D008055:Lipids; D000099252:Fatty Acid Amide Hydrolases