Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease

Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson's disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.

Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis

Autophagy and apoptosis are both highly regulated biological processes that play essential roles in tissue homeostasis, development and diseases. Autophagy is also described as a mechanism of death pathways, however, the precise mechanism of how autophagy links to cell death remains to be fully understood. Beclin 1 is a dual regulator for both autophagy and apoptosis. In this study we found that Beclin 1 was a substrate of caspase-3 with two cleavage sites at positions 124 and 149, respectively. Furthermore, the autophagosome formation occurred, followed by the appearance of morphological hallmarks of apoptosis after staurosporine treatment. The cleavage products of Beclin 1 reduced autophagy and promoted apoptosis in HeLa cells and the cells in which Beclin 1 was stably knocked down by specific shRNA. In addition, the cleavage of Beclin 1 resulted in abrogating the interaction between Bcl-2 with Beclin 1, which could be blocked by z-VAD-fmk. Thus, our results suggest that the cleavage of Beclin 1 by caspase-3 may contribute to inactivate autophagy leading towards augmented apoptosis.

On Social Participation and Reference of American Higher Education Management System / 中华医学教育探索杂志

This article analyzed the type,the significance,the role and the origin of the social participation of American higher education management,which is expected to play to the certain degree model function for the establishment of Chinese modem university system.

Inhibition of chloride channel currents in A549 cells by S2 protein of SARS coronavirus / 解放军医学杂志

Objective To study the effect of S2-protein from SARS coronavirus on the chloride channel currents in A549 cells and its possible cellular mechanisms. Methods The chloride channel currents were recorded in cultured A549 cells by using the whole-cell mode of patch clamp techniques. The experiments were divided into four groups: Control group: chloride channel currents were recorded in untreated A549 cells; S2 protein group: currents were recorded in A549 cells treated with S2 protein (final concentration 50?g/ml); calphostin C + S2 protein group: the effect of S2 protein on the currents in A549 cells pretreated with calphostin C (0.1mmol/L) for 10 minutes; SB203580+S2 protein group: the effect of S2 protein on the currents was examined with the solution containing SB203580 (20?mol/L). Results The currents of chloride channel in normal A549 cells showed outwardly rectifying properties and were insensitive to both TEA and amiloride, but were significantly inhibited both by SITS and DIDS (P