Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria

摘要: Abstract Mitochondria are central in the regulation of cell death. Apart from providing with ATP, mitochondria also harbor several death factors that released upon apoptotic stimuli. Alterations mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected Alzheimer's disease patients. These findings suggest may trigger abnormal onset neuronal disease. We previously reported presenilin 1 (PS1), which is often mutated familial forms disease, located hypothesized mutations sensitize cells to stimuli at level. Presenilin an active γ-secretase complex together Nicastrin (NCT), APH-1, PEN-2, among other substrates cleaves β-amyloid precursor protein (β-APP) generating amyloid β-peptide β-APP intracellular domain. Here we identified dual targeting sequences (for endoplasmic reticulum mitochondria) NCT showed expression immunoelectron microscopy. PS1 form a high molecular weight mitochondria. γ-Secretase activity isolated was demonstrated using C83 (α-secretase-cleaved C-terminal 83-residue fragment BD8 lacking thus activity) or recombinant C100-Flag (C-terminal 100-residue fragment) as substrates. Both systems generated APP domain, inhibited inhibitors l-685,458 Compound E. This novel localization NCT, PS1, PEN-2 expands role importance