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Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (PrP Sc ). Prion protein aggregation, misfolding, and cytotoxicity in the brain are the major causes of neuronal dysfunction and ultimate neurodegeneration in all TSEs. Parkin, an E3 ubiquitin ligase, has been studied extensively in all major protein misfolding aggregating diseases, especially Parkinson's disease and Alzheimer's disease, but the role of parkin in TSEs remains unknown. Here we investigated the role of parkin in a prion disease cell model in which neuroblastoma2a (N2a) cells were treated with prion peptide PrP106-126. We observed a gradual decrease in the soluble parkin level upon treatment with PrP106-126 in a time-dependent manner. Furthermore, endogenous parkin colocalized with FITC-tagged prion fragment106-126. Overexpression of parkin in N2a cells via transfection repressed apoptosis by enhancing autophagy. Parkin-overexpressing cells also showed reductions in apoptotic BAX translocation to the mitochondria and cytochrome c release to the cytosol, which ultimately inhibited activation of proapoptotic caspases. Taken together, our findings reveal a parkin-mediated cytoprotective mechanism against PrP106-126 toxicity, which is a novel potential therapeutic target for treating prion diseases.

Background Cyclin-dependent kinase-like 1 (CDKL1) is a member of cell division control protein 2 (CDC-2)-related serine threonine protein kinase family, and is reported to be overexpressed in malignant tumors such as breast cancer and gastric cancer. Objective This study aimed to evaluate the whether CDKL1 can serve as a potential molecular target for melanoma gene therapy. Methods CDKL1 expression in two melanoma cell lines, A375 and MV3 was measured by real-time PCR. To investigate the role of CDKL1 in cell growth of melanoma, we constructed CDKL1-siRNA expressing lentivirus and infected A375 and MV3 cells. The effects of RNAi-mediated CDKL1 downregulation on A375 and MV3 cell proliferation and colony-formation ability were detected by methylthiazoletetrazolium (MTT) assay and colony-formation assay. The effects of CDKL1 downregulation on A375 and MV3 cell cycle and apoptosis were analyzed by FACS analysis. Results Human melanoma cell lines A375 and MV3 expressed CDKL1 mRNA. Knockdown of CDKL1 in A375 and MV3 by CDKL1-siRNA lentivirus infection significantly inhibited cell growth and colony formation ability, promoted cell apoptosis, and arrested cells in G1 phase. Conclusion CDKL1 is associated with melanoma cell growth, colony formation, apoptosis, and cell cycle regulation. It may be considered as a valuable target for anti-melanoma therapeutic strategies. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1(PD-1) is an immune-inhibitory receptor expressed in activated T cells with PD-L1 and PD-L2 as two known ligands. Once PD-1 binds to PD-L1, it negatively regulates T-cell functions, including the effector functions of CD8 SP + sp T cells. Melanocyte-reactive T cell abundance was repressed, while Treg cells were enriched after PD-L1 fusion protein treatment. [Extracted from the article]