Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS
| Autor: | Nobuhiro Fujikake, Tomokatsu Yoshida, Akane Kyotani, Yoshitaka Nagai, Toshiki Mizuno, Morio Ueyama, Ikuko Mizuta, Yumiko Azuma, Masanori Nakagawa, Masamitsu Yamaguchi, Hiroshi Sasayama, Mai Shimamura, Takahiko Tokuda |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Central Nervous System
Valosin-containing protein Cell Cycle Proteins medicine.disease_cause Animals Genetically Modified Valosin Containing Protein Genetics medicine Animals Drosophila Proteins Compound Eye Arthropod Allele Amyotrophic lateral sclerosis Molecular Biology Gene Genetics (clinical) Motor Neurons Mutation Gene knockdown biology RNA-Binding Proteins General Medicine Compound eye medicine.disease Phenotype biology.protein RNA-Binding Protein FUS Drosophila Transcription Factor TFIID |
| Zdroj: | Human molecular genetics. 23(13) |
| ISSN: | 1460-2083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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