Elucidation of the fumctional network among the genes for familial Parkinson disease

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1) We have elucidated that PINK1 and Omi/HtrA2, PARK6 and PARK13 gene products, respectively, are co-localized in fee Lewy bodies. PINK1 and Qmi/HtrA2 are mitochondria-localizing protein kinase and serine protease, respectively, suggesting that mitochondrial proteins may be involved in the Lewy hody formation and/or sequestration of these PARK-related genes may contribute to the dopamin ergic neurode generation in sporadic Parkinson's disease.2) Parkin, the gene responsible for a familial form of Parkinson's disease (PD) termed autosomal recessive juvenile parkinsonism (AR-JP)/PARK2. Parkin has been shown to protect cells from endoplasmic reticulum (ER) and oxidative stressors presumably due to its ubiquitin ligase activity that targets proteins for proteasomal degradation. Although we showed that parkin is upregulated in response to ER stress, subsequent reports suggest that it does not represent a universal unfolded protein response (UPR). We report different regulation of parkin in … More response to ER stress in different cell lines, demonstrating upregulation of parkin as a cell type-specific response to ER stress. 2-mercaptoethanol (2-ME) and tunicamycin increased the expression of parkin in SH-SY5Y (H) cells, Neuro-2a cells, Goto-P3 cells, but not in SH-SY5Y (J) cells and IMR32 cells. In parallel with these studies, we also observed similar upregulation of the parkin coregulated gene (PACRG)/gene adjacent to parkin(Glup) by ER stress. Luciferase assays failed to show the transcriptional activation of 200bp parkin /Glup promoter in response to ER stress. These results indicate that induction of parkin by ER stress represents a cell type-specific response.3) We found that PINK1 forms complexes with Hsp90 and Cdc37/p50 in the cells. The protein stability of PINK1 was greatly reduced in the cells treated with either geldanamycin or novobiocin, inhibitors of Hsp90. Geldanamycin treatment led to the increased ubiquitination and the rapid degradation of PINK1 through the proteasome-dependent pathway. Furthermore, we found that L347P, a pathogenic mutant of PINK1, decreased the interaction with both Hsp90 and Cdc37/p50, and exhibited reduced protein stability compared with wild-type PINK1. These results strongly suggest that Hsp90 and Cdc37 are important factors regulating the stability of PINK1, which is involved in Parkinson s disease. Less