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

Abstract

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.

Mouse Models of PI(3,5)P2 Deficiency with Impaired Lysosome Function

“…Remarkably, the neuron-specific transgene was sufficient to rescue virtually all of the pathogenic effects of Fig4 deficiency, including juvenile lethality, size, tremor, spongiform degeneration, and accumulation of inclusion bodies in astrocytes. Although expression of Fig4 in the oligodendrocytes is absent in the NSE-Tg mice, the myelination deficit was rescued in CNS (Winters et al, 2011) and PNS (Ferguson et al 2012). In contrast, Fig4 expression in astrocytes corrected the accumulation of inclusion bodies but did not extend the lifetime of the Fig4 null mice (Fergusonet al 2012).…”

“…We evaluated the relative contributions of these two cell types to the neurological disorder by directing Fig4 cDNA expression specifically in neurons or astrocytes, using a neuron-specific promoter (NSE) or an astrocyte specific promoter (GFAP) (Ferguson et al, 2012). The tissue-specific transgenes were bred to the Fig4 null background and the phenotypes of the transgene-positive, Fig4 null mice were determined.…”

Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

“…These observations suggest that autophagy is a downstream pathway of PI(3,5)P 2 . Autophagy is similarly impaired by the inhibition of Fab1/PIKfyve function in mammalian cells [38, 42–44], in C. elegans [39] and in Drosophila [45]. Thus, the linkage between PI(3,5)P 2 and autophagy may be conserved.…”

The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease

“…Fig4 null mice reveal a dramatic reduction in myelin in the brain, spongiform degeneration, gliosis, and junvenile lethality (Nicholson et al, 2011; Winters et al, 2011; Ferguson et al, 2012). These neurological defects have been proposed to be caused by enlarged vacuoles in neurons, which may physically interfere with normal vesicular trafficking.…”