Fig4 Expression in the Rodent Nervous System and Its Potential Role in Preventing Abnormal Lysosomal Accumulation

Abstract

The phosphatase FIG4 regulates the concentration of phosphatidylinositol 3,5-diphosphate (PI3,5P2), a molecule critical for endosomal/lysosomal membrane trafficking and neuron function. We investigated Fig4 expression in the developing CNS of mice and rats using Western blot, real-time polymerase chain reaction, and morphological techniques in situ and in vitro and after spinal cord injury. Fig4 was expressed at a high levels throughout development in myelinating cells, particularly Schwann cells, and dorsal root ganglia sensory neurons. Fig4 protein and mRNA in CNS neurons were markedly diminished in adult versus embryonal animals. Spinal cord hemisection induced upregulation of Fig4 in adult spinal cord tissues that was associated with accumulation of lysosomes in neurons and glia. This accumulation appeared similar to the abnormal lysosomal storage observed in dorsal root ganglia of young fig4-null mice. The results suggest that Fig4 is involved in normal neural development and the maintenance of peripheral nervous system myelin. We speculate that adequate levels of Fig4 may be required to prevent neurons and glia from excessive lysosomal accumulation after injury and in neurodegeneration.

Abnormal junctions and permeability of myelin in PMP22‐deficient nerves

“…For teased nerve fiber immunohistochemistry, Western blot, electron microscopy (EM), plasmids, epithelial cell culture, and evaluation of tight junction electrical resistance and coimmuno-precipitation (co-IP), 8–10 please see the Supplementary Materials.…”

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

“…In mouse, Sac3/Fig4 RNA transcript is ubiquitously detected in all tissues, with highest level in the testes, spleen and heart(Chow et al, 2007), whereas Sac3/Fig4 protein level is highest in the brain (Guo et al, 2012; Sbrissa et al, 2007). The Vac14-Fig4-Fab1 ternary protein complex is also conserved in mammals and is responsible for the acute regulation of subcellular levels of PI(3,5)P 2 (Jin et al, 2008; Sbrissa et al, 2008).…”

Fig4 deficiency: A newly emerged lysosomal storage disorder?

“…This observation is consistent with the fact that Fig4 expression is persistently high in wild-type DRG sensory neurons throughout development and adulthood, but is only transiently high in spinal motor neurons during early development. By adulthood, Fig4/Sac3 expression is hardly detectable in wild-type spinal motor neurons (Guo et al , 2012). One might wonder how severe vacuolization can occur predominantly in sensory neurons, yet CMT4J patients typically do not complain about sensory symptoms.…”

“…This regulatory complex (PAS) is thought to localize on early endosomal membranes during the transition from early endosomes to late endosomes (Guo et al , 2012; Sbrissa et al , 2007; Yuan et al , 2007). Alongside the myriad of endosomal maturation processes that occur at this time, the PAS complex is suggested to mediate the conversion of early endosomal PI3P to late endosomal PI(3,5)P 2 - a conversion that appears to be essential for protein sorting and the trafficking of late endosomes to the degradative lysosomal compartment (Huotari and Helenius, 2011; Sbrissa et al , 2007).…”

“…Our studies have localized the Fig4/SAC3 protein to early endosomal membranes, where it may form the PI(3,5)P 2 regulatory complex with Vac14 and Fab1 in order to regulate early endosome-to-lysosome maturation (Guo et al , 2012). It has also been suggested that PI3P and PI(3,5)P 2 on early endosomal membranes are involved in the recruitment of ESCRT protein machinery that regulates the biogenesis of multi-vesicular bodies (intermediate organelles between early endosomes and late endosomes) (Bonangelino et al , 1997; Ho et al , 2012; Ikonomov et al , 2002b).…”