Study On Parkin, A Parkinson's Disease Related Protein

Parkinson's disease (PD) is the second most common neurodegenerative disorders after Alzheimer's disease and is characterized by a distinct set of motor symptoms, including tremor, muscle rigidity, postural instability and bradykinesia. Aging is the most risk factor in pathogenesis of PD which is estimated to affect approximately 1% of the population at 65 years and increased to 3% at 85. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and by the presence of Lewy bodies (LBs) and Lewy neurites in living neurons. Most of PD patients appear to be sporadic and just approximately 10-15% of PD patients are heriatable PD. Although the cause of PD is poorly understood, there is evidence that both environmental factors and genetic factors contribute to its development. Recently, several genes have been reported to be associated with the pathogenesis of familial forms of PD. Mutations or deletions of these genes leading to dysfunction of proteins are contributed to pathogenesis of PD.Autosomal recessive juvenile-onset parkinsonism (AR-JP) is a common familial forms of PD, and one notable distinct feature is early-onset before 40 years old. Mutations in the parkin gene have been reported to cause AR-JP. It has been shown that mutations in parkin account for nearly 50% of patients with the early-onset familial PD cases and more than 15% of sporadic PD cases with early onset. Parkin, also named PARK2, is an E3 ubiquitin ligase in ubiquitin-proteasome system (UPS). It works with El buiqui tin-activating enzyme and E2 ubiqui tin-conjugating enzyme to recognize specialy target proteins and enhances their degradation via UPS. So, searching for the new specific substrate of parkin is a hot spot in PD research. Recently, parkin has been reported to ubiquitinate particular protein substrate via its E3 ubiquitin ligase activity to change the substrate to degradation-independent role, and this may be important for molecular pathogenesis of parkin-linked PD.The ecukaryotic cells have two main protein degradation pathways:the ubiquitin-proteosome pathway and the autophagy-lysosome pathway. Previous studies have shown that the selective ablation of autophagy gene could directly cause neurodegenerative disease. An early report shows that autophagy is important for pathogenesis of PD. These results suggest that autophagy is associated with PD and neurodegeneration. A recent study indicates that in the neuronal cultures of midbrain from parkin null mice, markers of autophagy, such as LC3-â…¡/â… , are increased suggesting that knockout of parkin may induce autophagy. However, the links among parkin, autophagy and PD is still not clear. So, in this study, we focus on the relationship between parkin and autophagy.We report here that Bcl-2 is a novel substrate for the E3 ubiquitin ligase parkin. Parkin directly interactes with Bcl-2 specifically through its RING1-IBR-RING2 domain in C-terminus and mediates the mono-ubiquitination of Bcl-2. The mono-ubiquitination of Bcl-2 by parkin alters Bcl-2 turnover to increase its protein level. The increased Bcl-2 could bind more Beclin 1 to inhibit autophagy. The PD-linked mutant forms of parkin whose E3 ligase activity are selectively impaired, fail to regulate the mono-ubiquitination of Bcl-2.These results identify parkin as a novel regulator of autophagy through mono-ubiquitinating Bcl-2 and suggest a new way to understand the protect effects of parkin.