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Hum Mol Genet. 2018 Jul 15;27(14):2443-2453. doi: 10.1093/hmg/ddy145.

Protective role of the lipid phosphatase Fig4 in the adult nervous system.

Author information

1
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
2
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA.
3
Interdepartmental Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA.
4
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
5
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
6
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.

Abstract

The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varón syndrome. Constitutive Fig4-/- mice exhibit intention tremor, spongiform degeneration of neural tissue, hypomyelination, and juvenile lethality. To determine whether PI(3,5)P2 is required in the adult, we generated Fig4flox/-; CAG-creER mice and carried out tamoxifen-induced gene ablation. Global ablation in adulthood leads to wasting, tremor, and motor impairment. Death follows within 2 months of tamoxifen treatment, demonstrating a life-long requirement for Fig4. Histological examinations of the sciatic nerve revealed profound Wallerian degeneration of myelinated fibers, but not C-fiber axons in Remak bundles. In optic nerve sections, myelinated fibers appear morphologically intact and carry compound action potentials at normal velocity and amplitude. However, when iKO mice are challenged with a chemical white matter lesion, repair of damaged CNS myelin is significantly delayed, demonstrating a novel role for Fig4 in remyelination. Thus, in the adult PNS Fig4 is required to protect myelinated axons from Wallerian degeneration. In the adult CNS, Fig4 is dispensable for fiber stability and nerve conduction, but is required for the timely repair of damaged white matter. The greater vulnerability of the PNS to Fig4 deficiency in the mouse is consistent with clinical observations in patients with Charcot-Marie-Tooth disease.

PMID:
29688489
PMCID:
PMC6030899
DOI:
10.1093/hmg/ddy145
[Indexed for MEDLINE]
Free PMC Article

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