NUB1 suppresses the formation of Lewy body-like inclusions by proteasomal degradation of synphilin-1.

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.
Mesh Terms:
Binding Sites, Brain, Carrier Proteins, Cells, Cultured, Down-Regulation, Gene Expression Profiling, Guanidine, Humans, Lewy Bodies, Nerve Tissue Proteins, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Transport, RNA Interference, RNA, Messenger, Sodium Dodecyl Sulfate, Solubility, Solutions, Transcription Factors, Ubiquitins, Urea, Yeasts, alpha-Synuclein
Am. J. Pathol.
Date: Aug. 01, 2006
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