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Central nervous system dysfunction in a mouse model of FA2H deficiency.

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.

Pubmed ID: 21491498

Authors

  • Potter KA
  • Kern MJ
  • Fullbright G
  • Bielawski J
  • Scherer SS
  • Yum SW
  • Li JJ
  • Cheng H
  • Han X
  • Venkata JK
  • Khan PA
  • Rohrer B
  • Hama H

Journal

Glia

Publication Data

July 13, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: AG31675
  • Agency: NCRR NIH HHS, Id: C06 RR015455
  • Agency: NINDS NIH HHS, Id: NS056075
  • Agency: NINDS NIH HHS, Id: NS060807
  • Agency: NINDS NIH HHS, Id: NS43174
  • Agency: NIA NIH HHS, Id: R01 AG031675
  • Agency: NINDS NIH HHS, Id: R01 NS060807
  • Agency: NINDS NIH HHS, Id: R01 NS060807-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS060807-02
  • Agency: NINDS NIH HHS, Id: R01 NS060807-02S1
  • Agency: NINDS NIH HHS, Id: R01 NS060807-02S2
  • Agency: NINDS NIH HHS, Id: R01 NS060807-03
  • Agency: NINDS NIH HHS, Id: R01 NS060807-04
  • Agency: NINDS NIH HHS, Id: R01 NS060807-05
  • Agency: NINDS NIH HHS, Id: R03 NS056075
  • Agency: NINDS NIH HHS, Id: R03 NS056075-01
  • Agency: NINDS NIH HHS, Id: R03 NS056075-02
  • Agency: NCRR NIH HHS, Id: RR017677
  • Agency: NCRR NIH HHS, Id: RR16434

Mesh Terms

  • Amidohydrolases
  • Animals
  • Brain
  • Central Nervous System Diseases
  • Chromatography, Thin Layer
  • Demyelinating Diseases
  • Disease Models, Animal
  • Electromyography
  • Learning Disorders
  • Lipids
  • Maze Learning
  • Memory Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Motor Activity
  • Neural Conduction
  • Optic Nerve
  • Rotarod Performance Test
  • Spinal Cord
  • Tandem Mass Spectrometry