Synonyms: PS1, PS-1, S182, AD3
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.
- Going to Biomarker Extremes to Find Rare Alzheimer’s Variants
- Drug Company Halts Development of γ-Secretase Inhibitor Avagacestat
- Evidence Mounts That Some γ-Secretase Modulators Bind Presenilin
- Paris: Semagacestat Autopsy and Other News of Trial Tribulations
- First Crystal Structure of a Presenilin
- Presenilins and Calcium: A Lysosomal Stew With Acid Controversy
- Colombians Come to Fore in Alzheimer’s Research, Mass Media
- Evidence Piles Up for Presenilins’ Role in Autophagy
- Sole Perp—PS1 Alone Reconstitutes γ-Secretase Activity
- Research Brief: Presenilin Simplicity—Evidence for Autoproteolysis
- Notch Your Average Joe—Grounds for PS1 Neurogenesis Inhibition?
- Mouse of a Different Color: Presenilin Mutations Affect Melanin
- Familial Alzheimer's Presenilin Gene Perturbs Neurogenesis?
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