C-Abl Tyrosine Kinase Mediates Neurotoxic Prion Peptide-induced Neuronal Apoptosis And Its Mechanism

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are caused by infectious amyloid fibrils and pathologically characterized by brain vacuolation, neuronal cell death and microgliosis. The disease occurs in humans as Kuru, Creutzfeldt-Jakob disease (CUD), fatal familial insomnia (FFI) and Gerstamann Straussler Sheinker syndrome (GSS), in cattle as bovine spongiform encephalopathy, and in sheep and goats as scrapie. The main event associated with the pathogenesis of prion diseases is the conversion of the normal cellular prion proteins (PrPc) to the misfolded isoform PrPSc. The accumulation of abnormal forms of prion protein has been shown to be the main causative agent of these diseases.The c-Abl/p73pathway is also activated in the hippocampus of Alzheimer’s patients and murine models of AD, a well-known neurodegenerative disease involving oxidative stress. Studies have shown that a tyrosine kinase inhibitor enhances clearance of PrPSc via specific inhibition of c-Abl in prion-infected cell culture models, without influencing biogenesis, localization, or biochemical features of PrPc. Our research is to explain the role of oxidative stress in neurodegeneration disease and study the pathogenesi s of neurodegeneration disease1. We first established the standard curves for MST1, Foxo3, Bax and BIM using qPCR Plasmid Standardsandovercame the shortcomings in the traditional methods which had a low specificity and not easy to be standardized. These four standard curves laid good foundation for further qPCR analysis using SYBR Green I dye.2. PrP106-126peptide is neurotoxic and may contribute to neuron oxidative stress, based on that, a model of oxidative stress established by stimulating neuronal cells with PrP106-126. Knockdown of c-Abl using small interfering RNAprotected neuronal cells from PrP106-126-induced neuron apoptosis.And we reported that c-Abl tyrosine kinase as a novel upstream activator of MST1and BIM might play an important role in prion-induced neuron apoptosis via mitochondrial dysfunction.3.In this study, we also found that c-Ablknockdown by small interfering RNA protected neuronal cells from PrP106-126-induced mitochondrial dysfunction, production of reactive oxygen species, and apoptotic events inducing translocation of Bax to the mitochondria, cytochrome c release into the cytosol, and activation of caspase-9and caspase-3.Blocking the c-Abl tyrosine kinase also prevented neuronal cells from PrP106-126-induced apoptotic morphological changes.In conclusion, our findings suggested that c-Abl tyrosine kinase was involved in neurotoxic peptide-induced neuron apoptosis by mediatingmitochondrial homeostasis and therefore could be a potential therapeutic target for prion disease.