Parkinson’s disease (PD) is a prevalent neurodegenerative disease, clinically characterized by resting tremor, rigidity, bradykinesia, and postural instability. Degeneration of dopaminergic neurons in substantia nigra pars compacta and presence of Lewy bodies are the two pathologic hallmarks of PD. PD is primarily a sporadic disease, but 5-10% of PD cases are inherited. Loss-of-function mutations in parkin are associated with familial PD, especially early-onset PD. Parkin is an E3 ligase, which preserves cell functions against various toxic paradigms. Parkin binds to PICK1 (protein interacting with C-kinase 1), which is a peripheral membrane protein important for protein trafficking. PICK1 regulates the trafficking of receptors, channels, and transporters in neurons and other typ...[ Read more ]

Parkinson’s disease (PD) is a prevalent neurodegenerative disease, clinically characterized by resting tremor, rigidity, bradykinesia, and postural instability. Degeneration of dopaminergic neurons in substantia nigra pars compacta and presence of Lewy bodies are the two pathologic hallmarks of PD. PD is primarily a sporadic disease, but 5-10% of PD cases are inherited. Loss-of-function mutations in parkin are associated with familial PD, especially early-onset PD. Parkin is an E3 ligase, which preserves cell functions against various toxic paradigms. Parkin binds to PICK1 (protein interacting with C-kinase 1), which is a peripheral membrane protein important for protein trafficking. PICK1 regulates the trafficking of receptors, channels, and transporters in neurons and other types of cells. PICK1 is also involved in proacrosomal vesicle trafficking during spermiogenesis in testes, insulin granule trafficking in pancreatic beta-cells, and growth hormone secretion in brain.

Here we report that the BAR (Bin/Amphiphysin/Rvs) domain of PICK1 bound to the RING1 (really interesting new gene 1) domain of parkin and potently inhibited parkin E3 ligase activity by disrupting its interacting with UbcH7. The protein levels of several parkin substrates were reduced in young PICK1-knockout mice, but not altered in young PICK1/parkin double-knockout mice. PICK1 directly led to parkin aggresome formation independent of proteasome inhibition. Parkin translocated to damaged mitochondria in neurons and led to their degradation, whereas PICK1 potently prevented this process. PICK1 could also compromise parkin-mediated prevention of cell death. Young PICK1-knockout mice were resistant to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity, but this effect was abolished in young PICK1/parkin double-knockout mice. Taken together, reducing PICK1 could be potentially beneficial for treating PD by enhancing the protective effect of parkin.