Protective Role of Cell Division Cycle 48 (CDC48) Protein against Neurodegeneration via Ubiquitin-Proteasome System Dysfunction during Zebrafish Development

Cell division cycle 48 (CDC48), a ubiquitin-dependent molecular chaperone, is thought to mediate a variety of degradative and regulatory processes and maintain cellular homoeostasis. To investigate the protective function of CDC48 against accumulated ubiquitinated proteins during neurodevelopment, we developed an in vivo bioassay technique that detects expression and accumulation of fluorescent proteins with a polyubiquitination signal at the N terminus. When we introduced CDC48 antisense morpholino oligonucleotides into zebrafish embryos, the morphant embryos were lethal and showed defects in neuronal outgrowth and neurodegeneration, and polyubiquitinated fluorescent proteins accumulated in the inner plexiform and ganglion cell layers, as well as the diencephalon and mesencephalon, indicating that the degradation of polyubiquitinated proteins by the ubiquitin-proteasome system was blocked. These abnormal phenotypes in the morphant were rescued by CDC48 or human valosin-containing protein overexpression. Therefore, the protective function of CDC48 is essential for neurodevelopment. Background: CDC48, a ubiquitin-dependent molecular chaperone, mediates a variety of degradative and regulatory processes. Results: CDC48 deficiency produced lethal embryonic phenotypes, i.e. defects in neuronal outgrowth and neurodegeneration. Conclusion: The abnormal phenotypes in the morphant were not rescued by the catalytically inactive CDC48 mutant that had two impaired ATPase domains. Significance: CDC48 is essential for survival during neurodevelopment.