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Azuma, Y., Tokuda, T., Shimamura, M., Kyotani, A., Sasayama, H., Yoshida, T., Mizuta, I., Mizuno, T., Nakagawa, M., Fujikake, N., Ueyama, M., Nagai, Y., Yamaguchi, M. (2014). Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS.  Hum. Mol. Genet. 23(13): 3467--3480.
FlyBase ID
FBrf0225234
Publication Type
Research paper
Abstract

In humans, mutations in the fused in sarcoma (FUS) gene have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Cabeza (Caz) is the Drosophila ortholog of human FUS. Previously, we established Drosophila models of ALS harboring Caz-knockdown. These flies develop locomotive deficits and anatomical defects in motoneurons (MNs) at neuromuscular junctions; these phenotypes indicate that loss of physiological FUS functions in the nucleus can cause MN degeneration similar to that seen in FUS-related ALS. Here, we aimed to explore molecules that affect these ALS-like phenotypes of our Drosophila models with eye-specific and neuron-specific Caz-knockdown. We examined several previously reported ALS-related genes and found genetic links between Caz and ter94, the Drosophila ortholog of human Valosin-containing protein (VCP). Genetic crossing the strongest loss-of-function allele of ter94 with Caz-knockdown strongly enhanced the rough-eye phenotype and the MN-degeneration phenotype caused by Caz-knockdown. Conversely, the overexpression of wild-type ter94 in the background of Caz-knockdown remarkably suppressed those phenotypes. Our data demonstrated that expression levels of Drosophila VCP ortholog dramatically modified the phenotypes caused by Caz-knockdown in either direction, exacerbation or remission. Our results indicate that therapeutic agents that up-regulate the function of human VCP could modify the pathogenic processes that lead to the degeneration of MNs in ALS.

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Hum. Mol. Genet.
    Title
    Human Molecular Genetics
    Publication Year
    1992-
    ISBN/ISSN
    0964-6906
    Data From Reference
    Aberrations (1)
    Alleles (11)
    Genes (4)
    Human Disease Models (2)
    Natural transposons (1)
    Experimental Tools (1)
    Transgenic Constructs (9)