Characterization of PINK1, Parkin, and DJ-1, the causative genes of Parkinson's disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by dopaminergic (DA) neuronal loss in the substantia nigra pars compacta region. There have been many proposed models to explain the pathogenesis of PD. Above all, mitochondrial dysfunction and oxidative stresses are implicated as central players in PD pathogenesis. Among the genes with PD-causative mutations, PINK1 and Parkin have been shown to be important for mitochondrial function and quality control. I characterized 17 representative PINK1 pathogenic mutations. These mutations did not affect the typical cleavage patterns and subcellular localization of PINK1 under both normal and damaged-mitochondria conditions in mammalian cells. However, PINK1 mutations in the kinase domain failed to translocate Parkin to mitochondria and to induce mitochondrial aggregation. Consistent with the mammalian data, Drosophila PINK1 mutants with mutations in the kinase domain showed similar defects. Collectively, these results support the hypothesis that the kinase activity of PINK1 is essential for its function and for regulating downstream Parkin functions in mitochondria. In addition, I studied about DJ-1, another PD-causative gene, by elucidating the downstream signaling pathway of DJ-1 under oxidative stress condition. I found that DJ-1 protects DA neurons from oxidative stress by regulating the gene expression and subcellular localization of Daxx. Furthermore, I conducted a study of Mitofusins (Mfns) to understand the regulatory mechanism. Mfns play an essential role in mediating the mitochondrial outer membrane fusion, however the molecular mechanisms how the activity and function of Mfns are regulated have been elusive. I investigated the various post-translational modifications on Mfns. I found a highly conserved lysine residue (K357) on Mfns, which could be a putative post-translational modification site. Taken together, I revealed the function of PINK1, Parkin, and DJ-1 at the molecular and physiological level, and thereby suggest that both mitochondrial dysfunction and oxidative stresses contribute to PD occurrence. I believe that my research on the PD-causative genes and Mfns will provide insights to understand the pathogenic mechanisms of PD.