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Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production.
bioRxiv
November 2024
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.
Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer's disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes.
View Article and Find Full Text PDFS-Nitrosylation of p39 promotes its degradation and contributes to synaptic dysfunction induced by β-amyloid peptide.
Commun Biol
September 2024
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Alzheimer's disease (AD), characterized by cognitive decline, is increasingly recognized as a disorder marked by synaptic loss and dysfunction. Despite this understanding, the underlying pathophysiological mechanisms contributing to synaptic impairment remain largely unknown. In this study, we elucidate a previously undiscovered signaling pathway wherein the S-nitrosylation of the Cdk5 activator p39, a post-translational modification involving the addition of nitric oxide to protein cysteine residues, plays a crucial role in synaptic dysfunction associated with AD.
View Article and Find Full Text PDFHuperzine A Regulates the Physiological Homeostasis of Amyloid Precursor Protein Proteolysis and Tau Protein Conformation-A Computational and Experimental Investigation.
Biology (Basel)
July 2024
Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand.
The beneficial actions of the natural compound Huperzine A (Hup A) against age-associated learning and memory deficits promote this compound as a nootropic agent. Alzheimer's disease (AD) pathophysiology is characterized by the accumulation of amyloid beta (Aβ). Toxic Aβ oligomers account for the cognitive dysfunctions much before the pathological lesions are manifested in the brain.
View Article and Find Full Text PDFEvidence of γ-secretase complex involved in the regulation of intramembrane proteolysis in Entamoeba histolytica.
Parasitol Int
December 2024
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Presenilins (PSNs) are multifunctional membrane proteins involved in signal transduction, lysosomal acidification, and certain physiological processes related to mitochondria. The aspartic protease activity of PSN and the formation of a γ-secretase complex with other subunits such as nicastrin (NCT) are required for the biological functions. Although PSN is widely conserved in eukaryotes, most studies on PSN were conducted in metazoans.
View Article and Find Full Text PDFMolecular mechanism of substrate recognition and cleavage by human γ-secretase.
Science
June 2024
Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Key Laboratory for Protein Sciences of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43.
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