Non-Catalytic Roles of Presenilin Throughout Evolution

Grant Otto, Devdutt Sharma, Robin Williams

Research output: Contribution to journalLiterature reviewpeer-review


Research into Alzheimer’s disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β protein precursor and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins.
Original languageEnglish
Pages (from-to)1177-1187
Number of pages11
JournalJournal of Alzheimer's Disease
Issue number4
Publication statusPublished - 7 Jun 2016

Cite this