Tuesday, January 5, 2016

New fly models of FIG4-related diseases including Charcot-Marie-Tooth

Bharadwaj R, Cunningham KM, Zhang K, Lloyd TE. FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Hum Mol Genet. 2015 Dec 11. pii: ddv505. PMID: 26662798.

From the abstract: "FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, we generated Drosophila models of FIG4-related diseases. Fig4 null mutant animals are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. ... These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS."

1 comment:

  1. More on FIG4 in this study:

    Kyotani A, Azuma Y, Yamamoto I, Yoshida H, Mizuta I, Mizuno T, Nakagawa M, Tokuda T, Yamaguchi M. Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development. Exp Neurol. 2016 Mar;277:86-95.PMID: 26708557.