P75 Involved in the Ubiquitination of α-synuclein in Rotenone-based Parkinson's Disease Models.

For Parkinson's disease (PD), the regulatory mechanism of α-synuclein (α-syn) aggregation remains to be clarified. Ubiquitination modification is crucial for α-syn aggregation, with implications for Lewy body formation. Besides, ubiquitin ligase absentia homolog (siAH) is involved in the ubiquitination of α-syn. We investigated whether the p75 receptor can act as a potential regulator of α-syn accumulation through ubiquitination. Western blot, immunoprecipitation, gene transfection, and RNA interference technology were employed to detect the effect of p75 in in vivo and in vitro models. In a rotenone-based stereotactic (ST) infusion in vivo model of PD, p75 receptor and siAH expression was increased significantly compared with the control group. In cellular models of rotenone-mediated neurotoxicity, the interactions between p75 and siAH were revealed by immunoprecipitation; the colocalization of p75 with α-syn was observed in the cytoplasm; p75 promoted nuclear expression of NF-κB (p65), which might interact with the promoter of the siAH gene. Moreover, siRNA-mediated p75 depletion reduced the upregulation of α-syn and nuclear expression of p65 and protected against cell apoptosis induced by rotenone. Thus, aberrant expression of p75 may regulate the increased expression of α-syn, which is related to siAH-mediated ubiquitination and nuclear expression of p65.