＜Symposium III＞Nubopathies : NUB1-related neurodegenerative diseases

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NEDD8 ultimate buster-1 （NUB1） is a potent down-regulator of the ubiquitin-like protein NEDD8,because it directly interacts with NEDD8 and targets it and its conjugates to the 26S proteasome for proteolyticdegradation. Recently, we found that NUB1 physically interacts with synphilin-1 through its NEDD8-binding site,implying that NUB1 also targets synphilin-1 to the 26S proteasome for proteolytic degradation. Synphilin-1 is anα-synuclein-interacting protein and is a major component of inclusion bodies found in the brains of patients withneurodegenerative α-synucleinopathies, including Parkinson’s disease. In our recent studies, we immunostainedsections of brains from patients with Parkinson’s disease and other α-synucleinopathies and demonstrated thatNUB1, as well as synphilin-1, accumulates in the inclusion bodies. To defi ne the role of NUB1 in the formation ofthese inclusion bodies, we performed a co-transfection assay using cultured HEK293 cells. This assay showed thatNUB1 suppresses the formation of synphilin-1-positive inclusions. Further biochemical assays revealed that NUB1overexpression leads to the proteasomal degradation of synphilin-1. These results and our previous observationssuggest that NUB1 indeed targets synphilin-1 to the proteasome for its effi cient degradation, which, because of theresultant reduction in synphilin-1, suppresses the formation of synphilin-1-positive inclusions. In addition to thesebasic science aspects, our fi ndings on NUB1 have two important bearings clinically. First, they suggest that NUB1could serve as a neuropathological marker in patients with α-synucleinopathies because it is strongly accumulatedwith synphilin-1 in the inclusions of their brain cells. Second, they suggest that NUB1 could be a potential therapeutictarget for α-synucleinopathies.

＜Symposium III＞Nubopathies : NUB1-related neurodegenerative diseases

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