Presenilin-2 (PSEN2) is one of two highly homologous presenilin genes expressed in vertebrates. Presenilin-1 (PSEN1) has been more extensively studied in Alzheimer’s research because fewer mutations in PSEN2 are known. Mutations in the presenilin genes are the most common cause of familial Alzheimer’s disease, with more than 150 total mutations identified, of which about a dozen are in PSEN2. Mutations further differ from those in PSEN1 in that their onset age is somewhat later and their penetrance lower; that is, some mutation carriers do not develop Alzheimer’s disease.
Much information about these two proteins applies to both. Like presenilin-1, presenilin-2 forms the catalytic subunit of the γ-secretase complex that processes amyloid precursor protein (APP) and other integral membrane proteins. Comprising presenilin, nicastrin, aph-1, and pen-2, this large complex comprises one protein each of presenilin, nicastrin, aph-1, and pen-2; depending on which isoform of the four constituent proteins is used, this large complex occurs in different types. Besides presenilin, aph-1, too, comes in different forms, called aph-1a and aph-1b/c. Mice in which individual isoforms of these varying complex constituents have been deleted have different phenotypes. This suggests different substrate specificity of the respective complexes, giving clues to the differential function of presenilin-2 to presenilin-1. As part of γ-secretase, both presenilins can cleave APP to produce Aβ peptides and other proteolytic fragments, but the presenilins are thought to differ in their physiological roles. Presenilin-2 is generally expressed at lower levels than presenilin-1.
- Research Brief: Auguste D. Did Not Have Volga German Mutation
- ARF Notable Book: <i>The Thousand Mile Stare</i>, by Gary Reiswig
- Barcelona: Allosteric γ Modulation Moves Toward Clinic
- Barcelona: Live and Learn—γ-Secretase Inhibitors Fade, Modulators Rise
- De Strooper B, Iwatsubo T, Wolfe MS. Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease. Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006304. PubMed.
- Wolfe MS. Processive proteolysis by γ-secretase and the mechanism of Alzheimer's disease. Biol Chem. 2012 Sep;393(9):899-905. PubMed.
- Tomita T, Iwatsubo T. Structural biology of presenilins and signal peptide peptidases. J Biol Chem. 2013 May 24;288(21):14673-80. PubMed.
- St George-Hyslop P, Fraser PE. Assembly of the presenilin γ-/ε-secretase complex. J Neurochem. 2012 Jan;120 Suppl 1:84-8. PubMed.
- Tanzi RE. A Brief History of Alzheimer's Disease Gene Discovery. J Alzheimers Dis. 2012 Sep 17; PubMed.