Role of Cathepsin D in U18666A-induced Neuronal Cell Death POTENTIAL IMPLICATION IN NIEMANN-PICK TYPE C DISEASE PATHOGENESIS

摘要: Cathepsin D is an aspartyl protease that plays a crucial role in normal cellular functions and variety of neurodegenerative disorders, including Niemann-Pick type C (NPC) disease, which characterized by intracellular accumulation cholesterol glycosphingolipids many tissues, the brain. There evidence level activity cathepsin increased markedly vulnerable neurons NPC pathology, but its involvement neurodegeneration remains unclear. In present study, using mouse hippocampal cultured neurons, we evaluated significance toxicity induced U18666A, class II amphiphile, triggers cell death impairing trafficking cholesterol, as observed pathology. Our results showed U18666A-mediated accompanied increase mRNA enzyme decrease total peptide content. The cytosolic D, on other hand, was along with cytochrome c activated caspase-3 U18666A-treated neurons. inhibitor, pepstatin A, partially protected against attenuating these signaling mechanisms. Additionally, down-regulation prevented, whereas overexpression increased, vulnerability N2a cells to U18666A-induced toxicity. We also extracellular from or application exogenous can induce neurotoxicity activating autophagic pathway. These suggest release/activation trigger possibly development Thus, targeting level/activity may provide new therapeutic opportunity for treatment Background: has been implicated associated accumulation. Results: Increased levels enhanced neuronal via different Conclusion: Leakage within outside cause death. Significance: be involved degeneration