| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Formation of intracellular inclusion bodies due to defects in the protein degradation machinery is associated with the pathogenesis of neurodegenerative diseases. Sequestosomal protein p62, which is an oxidative stress-related protein and a ubiquitin-binding protein, is a component protein of Lewy bodies that are observed in patients with Parkinson's disease. The association of p62 with poly-ubiquitinated proteins may be an important step in the formation of intracellular protein aggregates like Lewy bodies. To study the role of p62 in the formation of protein aggregates in PC12 cells, we monitored the intracellular localizations of p62 and ubiquitinated proteins and the levels of both components during treatment with proteasome inhibitor. In the stage of aggregate formation, p62 and ubiquitin were co-localized. After the treatment of the cells with proteasome inhibitor, we found that the expression level of p62 increased due to the transcriptional activation of the gene. Both the transcriptional inhibitor actinomycin D and an antisense oligonucleotide of p62 inhibited the proteasome inhibitor-mediated increase of p62, the sequestration of ubiquitinated proteins, and the enlargement of the aggregates. Furthermore, p62-positive aggregates were observed primarily in surviving cells. Together, these results suggest that p62 plays an important role in the protection of cells from the toxicity of misfolded proteins by enhancing aggregate formation.
We reported a novel cytoprotective mechanism of deprenyl involving PI3K and Nrf2-mediated induction of p62 and oxidative stress-related proteins. Deprenyl increased the expression of p62, as well as HO-1, PrxI,TrxI,TrxRxI, and γ GCS in SH-SY5Y cells. This result suggests that the cytoprotective effect of deprenyl is, in part, dependent on Nrf2-mediated induction of p62 and antioxidative proteins.
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