Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.
Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.
Center for Human Genetics, Leuven Institute for Neurodegenerative Diseases, KULeuven, 3000 Leuven, Belgium; Department of Molecular and Developmental Genetics, VIB, 3000, Leuven, Belgium.
Bart
B
De Strooper
Takeshi
T
Iwatsubo
Michael S
MS
Wolfe
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D053763:Presenilins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D051880:Receptors, Notch / Q000502:physiology; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053763:Presenilins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases