Fig4 deficiency: a newly emerged lysosomal storage disorder?

Abstract

FIG4 (Sac3 in mammals) is a 5'-phosphoinositide phosphatase that coordinates the turnover of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P(2)), a very low abundance phosphoinositide. Deficiency of FIG4 severely affects the human and mouse nervous systems by causing two distinct forms of abnormal lysosomal storage. The first form occurs in spinal sensory neurons, where vacuolated endolysosomes accumulate in perinuclear regions. A second form occurs in cortical/spinal motor neurons and glia, in which enlarged endolysosomes become filled with electron dense materials in a manner indistinguishable from other lysosomal storage disorders. Humans with a deficiency of FIG4 (known as Charcot-Marie-Tooth disease type 4J or CMT4J) present with clinical and pathophysiological phenotypes indicative of spinal motor neuron degeneration and segmental demyelination. These findings reveal a signaling pathway involving FIG4 that appears to be important for lysosomal function. In this review, we discuss the biology of FIG4 and describe how the deficiency of FIG4 results in lysosomal phenotypes. We also discuss the implications of FIG4/PI(3,5)P(2) signaling in understanding other lysosomal storage diseases, neuropathies, and acquired demyelinating diseases.

Figure 1

A. A diagram of phosphotidylinositide metabolism. PI = phosphotidylinositol. Relevant enzymes to this paper are marked. Their related diseases are shown in parenthess. Notice that all pathways involved in 4-phosphate are simplified since they are not relevant to this review. B. A hypothetical mechanism in Fig4 deficiency is illustrated.

Figure 2

Vacuoles in plt neurons of the DRG. (A) A semithin section was processed from the DRG of a 5-week-old wild-type mouse. The DRG is filled with sensory neurons with a polygon shape and pale nucleus. There are a few myelinated nerve fibers visible between the neurons. (B) The same study was done in the DRG of a 5-week-old plt mouse. Many vacuoles are visible in the neurons (arrowhead). The cytoplasm in some neurons is fully occupied by these vacuoles. (C) Two adjacent vacuoles were examined under electron microscopy, and were determined to be single-membrane bound. Vacuoles have a watery appearance. They contain oil-drop-like materials. A few pieces of membranous debris may occasionally be seen in the vacuoles. (D) A semithin section of DRG from a wild-type mouse at P4 was imaged under light microscopy (scale bar = 20 µm). (E) Large vacuoles in plt DRG neurons are readily identifiable at P4 (arrows). Note: Reprinted with permission from “Distinct pathogenic processes between Fig4- deficient motor and sensory neurons,” by Katona et al., 2011, European Journal of Neuroscience, 33, pp. 1401-1410.

Figure 3

Mouse spinal cord and brain were dissected for electron microscopy. (A) A motor neuron was identified from the spinal anterior horn of a wild-type mouse. The sizes of many motor neurons are larger than those in the plt anterior horns. This motor neuron contains electron-dense granules (arrow). However, these granules are small and scattered throughout the cytoplasm, rather than clustered in the perinuclear region. (B) In contrast, these high electron dense granules are found in many plt neurons and/or glia. They are numerous and always clustered in the perinuclear region (arrow). Granules are not detectable in axons (asterisk). (C) Granules were inspected under high magnification. They are inhomogeneous. Large granules appear to be fused from several dark vesicles. (D) Similar accumulations were observed in cerebral neurons. Note: Reprinted with permission from “Distinct pathogenic processes between Fig4-deficient motor and sensory neurons,” by Katona et al., 2011, European Journal of Neuroscience, 33, pp. 1401-1410.

Figure 4

Segmental demyelination in teased sciatic nerve fibres from plt mice. Mouse sciatic nerves were teased into individual nerve fibers and stained via immunohistochemistry. (A) Myelin specific protein MAG is strongly expressed in Schmidt-Lanterman incisures. MAG staining is absent in some segments of myelinated plt nerve fibers (e.g. between arrowheads in A,B). Labeling for NFp (phosphorylated neurofilaments) was intact in the same segment (C), demonstrating segmental demyelination. Many nuclei are lined up along this segment of the axon (D) that are derived from invading macrophages or remyelinating Schwann cells. Demyelination was not observed in wild-type nerve fibers. Note. Reprinted with permission from “Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration,” by Zhang et al., 2008, Brain, 131, pp.1990-2001.