Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons

The p75 neurotrophin receptor regulates neuronal survival, promoting it in some contexts yet activating apoptosis in others. The mechanism by which the receptor elicits these differential effects is poorly understood. Here, we demonstrate that p75 is cleaved by gamma-secretase in sympathetic neurons, specifically in response to proapoptotic ligands. This cleavage resulted in ubiquitination and subsequent nuclear translocation of NRIF, a DNA binding protein essential for p75-mediated apoptosis. Inhibition of gamma-secretase or expression of a mutant p75 resistant to this protease prevented receptor proteolysis, blocked NRIF nuclear entry, and prevented apoptosis. In contrast, overexpression of the p75 ICD resulted in NRIF nuclear accumulation and apoptosis. The receptor proteolysis and NRIF nuclear localization were also observed in vivo during naturally occurring cell death in the superior cervical ganglia. These results indicate that p75-mediated apoptosis requires gamma-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF

XAF1 promotes neuroblastoma tumor suppression and is required for KIF1B?-mediated apoptosis

10.18632/oncotarget.8748Oncotarget72334229-3423

The Potential for Estrogens in Preventing Alzheimer's Disease and Vascular Dementia

Estrogens are the best-studied class of drugs for potential use in the prevention of Alzheimer's disease (AD). These steroids have been shown to be potent neuroprotectants both in vitro and in vivo, and to exert effects that are consistent with their potential use in prevention of AD. These include the prevention of the processing of amyloid precursor protein (APP) into beta-amyloid (Aß), the reduction in tau hyperphosphorylation, and the elimination of catastrophic attempts at neuronal mitosis. Further, epidemiological data support the efficacy of early postmenopausal use of estrogens for the delay or prevention of AD. Collectively, this evidence supports the further development of estrogen-like compounds for prevention of AD. Several approaches to enhance brain specificity of estrogen action are now underway in an attempt to reduce the side effects of chronic estrogen therapy in AD