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FIG4 is a ubiquitously expressed phosphatase that, in complex with FAB1/PIKFYVE and VAC14, regulates the biosynthesis of the signaling lipid PI(3,5)P 2 . Null mutation of  Fig4  in the mouse results in spongiform degeneration of brain and peripheral ganglia, defective myelination and juvenile lethality. Partial loss-of-function of human  FIG4  results in a severe form of Charcot–Marie–Tooth neuropathy. Neurons from null mice contain enlarged vacuoles derived from the endosome/lysosome pathway, and astrocytes accumulate proteins involved in autophagy. Other cellular defects include astrogliosis and microgliosis. To distinguish the contributions of neurons and glia to spongiform degeneration in the  Fig4  null mouse, we expressed  Fig4  under the control of the neuron-specific enolase promoter and the astrocyte-specific glial fibrillary acidic protein promoter in transgenic mice. Neuronal expression of  Fig4  was sufficient to rescue cellular and neurological phenotypes including spongiform degeneration, gliosis and juvenile lethality. In contrast, expression of  Fig4  in astrocytes prevented accumulation of autophagy markers and microgliosis but did not prevent spongiform degeneration or lethality. To confirm the neuronal origin of spongiform degeneration, we generated a floxed allele of  Fig4  and crossed it with mice expressing the Cre recombinase from the neuron-specific synapsin promoter. Mice with conditional inactivation of  Fig4  in neurons developed spongiform degeneration and the full spectrum of neurological abnormalities. The data demonstrate that expression of  Fig4  in neurons is necessary and sufficient to prevent spongiform degeneration. Therapy for patients with  FIG4  deficiency will therefore require correction of the deficiency in neurons.

Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration