Mutations in the lipid phosphatase Fig4 are associated with multiple neurodegenerative diseases including a rare and severe form of Charcot-Marie-Tooth disease known as type 4J (CMT4J). CMT4J has been attributed to dysregulation of the production and turnover of Fig4’s lipid substrate, the phosphoinositide signaling lipid, PI3,5P2 through disruption of its well characterized protein complex, the Fab1-Vac14-Fig4 complex. Fig4 is known to play roles in the cell independent of its catalytic function. Our work in yeast suggests that the presence of Fig4 in cells can confer a growth advantage under stress and that this growth advantage is conferred in a dominant manner, independent of Fig4 catalytic activity or its participation in the Fab1-Vac14-Fig4 complex. Importantly, we have found that Fig4 variants associated with multiple demyelinating diseases, including those involved in CMT4J, leukodystrophy and amyotrophic lateral sclerosis (ALS), display similar behavior. These data suggest that Fig4 influences cellular homeostasis, and perhaps human disease, through multiple pathways.
This work is supported by a Max and Minnie Tomerlin Voelcker Fund Young Investigator Award and NIGMS R00 GM 120511-03
