Creutzfeldt-Jakob Disease Subtype-Specific Regional and Temporal Regulation of ADP Ribosylation Factor-1-Dependent Rho/MLC Pathway at Pre-Clinical Stage

摘要: Small GTPases of the Arf family mainly activate formation coated carrier vesicles. We showed that class-I Arf1 interacts specifically with full length GPI-anchored cellular prion protein (PrPC). Several recent reports have also demonstrated a missing link between endoplasmic reticulum and Golgi-complex role for proper folding, but exact molecular mechanism is not yet fully understood. In present study, we identified characterized interactive during PrPC intracellular distribution under pathophysiological conditions. interaction was investigated in cortical primary neuronal cultures wild type knockout mice (PrP−/−). co-binding affinity confirmed using reverse co-immunoprecipitation, co-localization confocal laser-scanning microscopy. Treatment brefeldin-A modulated expression resulted down-regulation redistribution into cytosolic region. pre-symptomatic stage disease, significantly downregulated frontal cortex tg340 expressing about fourfold human PrP-M129 PrP null background had been inoculated sCJD MM1 brain tissue homogenates (sCJD mice). addition, CJD significant binding capacity co-immunoprecipitation analysis. examined patients subtypes VV2 found it regulated region-specific manner. cortex, changed either or subtype. Interestingly, reduced cerebellum both as compared to controls. Furthermore, observed altered RhoA activity, which turn affects myosin light-chain (MLC) phosphorylation Arf1-dependent PI3K pathway. Together, our findings underscore key early symptomatic neurodegeneration. Targeting Arf/Rho/MLC signaling axis might be promising strategy uncover probably influences disease progression internal homeostasis misfolded proteins.