Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra and formation of intracellular inclusions known as Lewy bodies in remaining cells. Despite recent development in PD research, rigorous biomarkers for pre-symptomatic diagnosis of PD are not available. Elucidation of the molecular basis of PD pathogenesis will facilitate the search of these biomarkers to allow early treatment. In addition to common sporadic PD, there exist rare familial forms of Parkinsonism, usually characterized by earlier age of onset and, in some cases, absence of typical Lewy body Abbreviations used: HtrA2, high temperature requirement serine protease 2; IKK, IjBa kinase; JNK, c-Jun NH 2 -terminal kinase; NF-jB, nuclear factor-jB; PanK2, pantothenate kinase 2; PD, Parkinson's disease; PI3-kinase, phosphatidylinositol-3 kinase; PINK1, PTEN-induced kinase 1; PTEN, phosphatase and tensin homologue deleted on chromosone 10; PTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; siRNA, small interfering RNA; TIM, translocase of the inner membrane; TRAF, tumor necrosis factor receptor-associated factor; TRAP, tumor necrosis factor receptor-associated protein.
AbstractMutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism. To decipher the role of PINK1 in pathogenesis of Parkinson's disease (PD), researchers need to identify protein substrates of PINK1 kinase activity that govern neuronal survival, and establish whether aberrant regulation and inactivation of PINK1 contribute to both familial Parkinsonism and idiopathic PD. These studies should take into account the several unique structural and functional features of PINK1. First PINK1 is a rare example of a protein kinase with a predicted mitochondrial-targeting sequence and a possible resident mitochondrial function. Second, bioinformatic analysis reveals unique insert regions within the kinase domain that are potentially involved in regulation of kinase activity, substrate selectivity and stability of PINK1. Third, the C-terminal region contains functional motifs governing kinase activity and substrate selectivity. Fourth, accumulating evidence suggests that PINK1 interacts with other signaling proteins implicated in PD pathogenesis and mitochondrial dysfunction. The most prominent examples are the E3 ubiquitin ligase Parkin, the mitochondrial protease high temperature requirement serine protease 2 and the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1. How PINK1 may regulate these proteins to maintain neuronal survival is unclear. This review describes the unique structural features of PINK1 and their possible roles in governing mitochondrial import, processing, kinase activity, substrate selectivity and stability of PINK1. Based upon the findings of previous studies of PINK1 function in cell lines and animal models, we propose a model on the neuroprotective mechanism of PINK1. This model may serve as a conceptual framework...