Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by bradykinesia, rigidity, resting tremor and postural instability. The death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LB) are prominent pathologic features of PD. Although studies of environmental toxins, identification of genes associated with familial PD and establishment of mouse models have provided novel insights into the molecular pathogenesis of PD, the etiology of PD is still not fully understood. Parkin, mutation of which is the most frequent cause of recessive PD, encodes a multifunctional E3 ubiquitin ligase-Parkin. Parkin plays an essential role in selective autophagy of damaged mitochondria, which is also known as mitophagy....[ Read more ]

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by bradykinesia, rigidity, resting tremor and postural instability. The death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LB) are prominent pathologic features of PD. Although studies of environmental toxins, identification of genes associated with familial PD and establishment of mouse models have provided novel insights into the molecular pathogenesis of PD, the etiology of PD is still not fully understood. Parkin, mutation of which is the most frequent cause of recessive PD, encodes a multifunctional E3 ubiquitin ligase-Parkin. Parkin plays an essential role in selective autophagy of damaged mitochondria, which is also known as mitophagy. In addition, a failure to eliminate dysfunctional mitochondria is implicated in the pathogenesis of PD. In cultured hippocampal or cortical neurons, mitochondrial damage could be induced by acute treatment with the mitochondrial membrane potential uncoupler CCCP (Carbonyl cyanide 3-chlorophenylhydrazone) or chronic treatment with mitochondrial complex I inhibitor rotenone. We found that PICK1 (Protein interacting with C-kinase 1) could be cleaved by caspases during apoptosis caused by mitochondrial damage. Cleaved PICK1 could cluster Parkin when both were overexpressed in COS7 cells, HEK 293T cells and cultured hippocampal neurons. More importantly, cleaved PICK1 could delay Parkin’s translocation to mitochondria in COS7 cells treated with CCCP and therefore could interfere with Parkin’s role in clearing damaged mitochondria. Consistently, PICK1 exists in SNpc where cell bodies of dopaminergic neurons locate. All together, this study suggests a potential role of cleaved PICK1 in the pathogenesis of PD by participating in Parkin-mediated mitophagy.