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(American Journal of Pathology. 2006;169:553-565.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051067

NUB1 Suppresses the Formation of Lewy Body-Like Inclusions by Proteasomal Degradation of Synphilin-1

Kunikazu Tanji*, Tomoaki Tanaka*{dagger}, Fumiaki Mori{ddagger}, Katsumi Kito§, Hitoshi Takahashi, Koichi Wakabayashi{ddagger} and Tetsu Kamitani*

From the Department of Cardiology,* The University of Texas M.D. Anderson Cancer Center, Houston, Texas; the Department of Urology,{dagger} Osaka City University School of Medicine, Osaka, Japan; the Department of Neuropathology,{ddagger} Hirosaki University School of Medicine, Hirosaki, Japan; the First Department of Pathology,§ Ehime University School of Medicine, Ehime, Japan; and the Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan

NUB1 is a potent down-regulator of the ubiquitin-like protein NEDD8, because it targets NEDD8 to the proteasome for proteolytic degradation. From results in this study, we found that NUB1 physically interacts with synphilin-1 through its NEDD8-binding site, implying that NUB1 also targets synphilin-1 to the proteasome for degradation. Synphilin-1 is a major component of inclusion bodies found in the brains of patients with neurodegenerative {alpha}-synucleinopathies, including Parkinson’s disease. In this study, we immunostained sections of brains from patients with Parkinson’s disease and other {alpha}-synucleinopathies and demonstrated that NUB1, as well as synphilin-1, accumulates in the inclusion bodies. To define the role of NUB1 in the formation of these inclusion bodies, we performed a co-transfection assay using cultured HEK293 cells. This assay showed that NUB1 suppresses the formation of synphilin-1-positive inclusions. Further, biochemical assays revealed that NUB1 overexpression leads to the proteasomal degradation of synphilin-1. These results and our previous observations suggest that NUB1 indeed targets synphilin-1 to the proteasome for its efficient degradation, which, because of the resultant reduction in synphilin-1, suppresses the formation of synphilin-1-positive inclusions.




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