老年痴呆症 z-bo 2020-09-18 355

　　Researchers from Tsinghua University confirmed that the archaeal presenilin homolog PSH can cleave amyloid precursor protein (APP) like human γ-secretase.

　　Professor Yigong Shi of Tsinghua University is the corresponding author of this paper. Yigong Shi’s research group is mainly dedicated to the use of structural biology and biochemistry to study the molecular mechanisms of tumorigenesis and apoptosis, focusing on the structure and function of tumor suppressor and apoptosis regulatory proteins, and major disease-related membrane proteins The study of the structure and function of the cell, the structure and function of the intracellular biological macromolecular machinery. After returning to China, Shi Yigong published many papers in top international journals such as Nature. At the same time, he also built a bridge for talent introduction with Tsinghua University as the center.

　　One of the important pathogens leading to Alzheimer's disease (senile dementia) is the accumulation of β-Amyloid (Aβ) polypeptide. Aβ is derived from APP and is finally generated by APP after several shearing. APP is initially cleaved by β-secretase in the extracellular space into a fragment called APP C99. APP C99 is then continuously cleaved by γ-secretase to finally generate Aβ42/Aβ40/Aβ38.

　　230-kDa γ-secretase is not a single subunit protein, but consists of four subunits, including Presenilin, Aph-1, Pen-2 and Nicastrin (NCT). One of the important roles is the presenilin active catalytic subunit. Currently, more than 200 pathogenic presenilin mutations have been discovered, which makes the regulation of γ-secretase activity a potentially attractive therapeutic strategy. Unfortunately, some technical challenges in the expression and biochemical manipulation of γ-secretase prevented the discovery of γ-secretase modulators.

　　In this article, researchers report that similar to γ-secretase, the archaeal presenilin homolog PSH can faithfully process the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of PSH cleavage products Aβ42 to Aβ40 is almost the same as that of γ-secretase.

　　Researchers have confirmed that some presenilin inhibitors can specifically inhibit the proteolytic activity of PSH. Some known modulators of γ-secretase can also regulate PSH and affect the ratio of Aβ42/Aβ40. In addition, they also analyzed the crystal structure of the combination of PSH and a known γ-secretase inhibitor, and the results showed that the inhibitor separated the two catalytic aspartic acid residues of PSH. This binding mode explains how the inhibitor inhibits PSH protease activity, indicating that human presenilin also has a similar mechanism.

　　"These research results confirm that PSH can be used as an excellent alternative protease for γ-secretase for screening drugs that can regulate protease activity and γ-secretase cleavage preference.