Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS.
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.
Department of Neurology and.
Yumiko
Y
Azuma
Department of Neurology and Department of Molecular Pathobiology of Brain Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan ttokuda@koto.kpu-m.ac.jp.
Takahiko
T
Tokuda
Department of Applied Biology and Insect Biomedical Research Center, Kyoto Institute of Technology, Hashikami-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Mai
M
Shimamura
Department of Applied Biology and Insect Biomedical Research Center, Kyoto Institute of Technology, Hashikami-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Akane
A
Kyotani
Department of Neurology and.
Hiroshi
H
Sasayama
Department of Neurology and.
Tomokatsu
T
Yoshida
Department of Neurology and.
Ikuko
I
Mizuta
Department of Neurology and.
Toshiki
T
Mizuno
Department of Neurology and.
Masanori
M
Nakagawa
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
Nobuhiro
N
Fujikake
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
Morio
M
Ueyama
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
Yoshitaka
Y
Nagai
Department of Applied Biology and Insect Biomedical Research Center, Kyoto Institute of Technology, Hashikami-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Masamitsu
M
Yamaguchi
D000818:Animals; D030801:Animals, Genetically Modified; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D054910:Compound Eye, Arthropod / Q000378:metabolism / Q000473:pathology; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; D035362:Transcription Factor TFIID; C094754:caz protein, Drosophila; D000074405:Valosin Containing Protein; C585179:ter94 protein, Drosophila