Presenilins were originally identified as the genes harboring mutations that cause autosomal-dominant Alzheimer’s disease. Such mutations occur in both presenilin-1 and its homolog presenilin-2, but the former are far more numerous. The presenilin proteins are large multi-pass transmembrane proteins that form the catalytic core of the membrane-embedded γ-secretase complex. This complex also contains the proteins nicastrin, aph-1, and pen-2, and subserves a multitude of cell signaling functions by way of regulated intramembrane proteolysis.
Gamma-secretase cleaves many different type I integral membrane proteins, most prominently APP and Notch. It does so in a characteristic, processive fashion that releases Aβ peptides of different lengths. The primary pathogenic mechanism of the presenilin mutations involves subtle changes to these processive cleavage steps that shifts Aβ generation toward longer, more aggregation-prone peptides (e.g., more Aβ42, less Aβ38).
Intracellularly, presenilins occur in endosomes, the trans-Golgi network, and the endoplasmic reticulum, where presenilin-1 is thought to facilitate cellular protein trafficking and to regulate calcium homeostasis. Presenilin-1 and presenilin-2, which share 67 percent sequence identity, have distinct but overlapping functions in the brain. Presenilin-1 may play a larger role in development, as knockout mice have severe skeletal and brain abnormalities and die soon after birth, whereas presenilin-2 knockout mice are viable. Mouse models of pathogenic presenilin-1 mutations exist; when crossed with human mutant APP mouse strains, they tend to increase amyloid pathology. In addition, these mice model the established increase in the AD biomarker CSF tau, as well as some synaptic and behavioral phenotypes; however, they do not reflect the full course of Alzheimer’s disease.
Gamma-secretase is a leading target of drug discovery research. Thus far, all small-molecule inhibitors have failed in part because they also inhibit Notch cleavage; the current focus is on small-molecule modifiers that shift Aβ production without affecting Notch. Because Notch signaling has a role in tumor suppression, presenilins are also associated with cancer.
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- Research Brief: Presenilin Simplicity—Evidence for Autoproteolysis
- Notch Your Average Joe—Grounds for PS1 Neurogenesis Inhibition?
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