Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS

Journal Article · Mon Oct 15 04:00:00 EDT 2018 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2018.08.001· OSTI ID:23082560

Azuma, Yumiko ^[1]; Tokuda, Takahiko ^[1]; Kushimura, Yukie ^[1]; Yamamoto, Itaru ^[2]; Mizuta, Ikuko ^[1]; others, and

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1. Departments of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566 (Japan)
2. Department of Applied Biology, Kyoto Institute of Technology, Hashikami-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan)

Highlights: • Mutation in Hippo suppressed aberrant eye morphology induced by Cabeza knockdown. • Mutation in Hippo suppressed neuron-specific defects induced by Cabeza knockdown. • Mutation in Hippo restored Cabeza protein in the nucleus. • Hippo mRNA level increased in Cabeza knockdown. • Cabeza may negatively regulate hippo. Mutations in the Fused in Sarcoma (FUS) gene have been identified in familial ALS in human. Drosophila contains a single ortholog of human FUS called Cabeza (Caz). We previously established Drosophila models of ALS targeted to Caz, which developed the locomotive dysfunction and caused anatomical defects in presynaptic terminals of motoneurons. Accumulating evidence suggests that ALS and cancer share defects in many cellular processes. The Hippo pathway was originally discovered in Drosophila and plays a role as a tumor suppressor in mammals. We aimed to determine whether Hippo pathway genes modify the ALS phenotype using Caz knockdown flies. We found a genetic link between Caz and Hippo (hpo), the Drosophila ortholog of human Mammalian sterile 20-like kinase (MST) 1 and 2. Loss-of-function mutations of hpo rescued Caz knockdown-induced eye- and neuron-specific defects. The decreased Caz levels in nuclei induced by Caz knockdown were also rescued by loss of function mutations of hpo. Moreover, hpo mRNA level was dramatically increased in Caz knockdown larvae, indicating that Caz negatively regulated hpo. Our results demonstrate that hpo, Drosophila MST, is a novel modifier of Drosophila FUS. Therapeutic targets that inhibit the function of MST could modify the pathogenic processes of ALS.

• OSTI ID: 23082560
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 371; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DROSOPHILA
EYES
HUMAN POPULATIONS
MESSENGER-RNA
NERVE CELLS
PHOSPHOTRANSFERASES
SARCOMAS