Central nervous system dysfunction in a mouse model of Fa2H deficiency

Kathleen A. Potter, Michael J. Kern, George Fullbright, Jacek Bielawski, Steven S. Scherer, Sabrina W. Yum, Jian J. Li, Hua Cheng, Xianlin Han, Jagadish Kummetha Venkata, P. Akbar Ali Khan, Bärbel Rohrer, Hiroko Hama

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


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 Fa2hflox/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 Fa2hflox/flox Cnp1-Cre mice were indistinguishable from Fa2h-/- mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2hflox/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.

Original languageEnglish (US)
Pages (from-to)1009-1021
Number of pages13
Issue number7
StatePublished - Jul 2011
Externally publishedYes


  • Fatty acid 2-hydroxylase
  • Leukodystrophy
  • Oligodendrocytes

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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