Laboratory for Membrane Trafficking
The Laboratory for Membrane Trafficking is focused on understanding the molecular biology of membrane transport in a disease-related context covering Alzheimer’s disease and congenital disorders of glycosylation type II.
Our laboratory is focused on understanding the molecular biology of membrane transport in a disease-related context covering Alzheimer’s disease and congenital disorders of glycosylation type II.
Related to Alzheimer’s, APP cleavage by gamma-secretase leads to amyloid beta peptide production, one possible cause of Alzheimer’s symptoms. gamma-secretase is composed of four proteins – presenilin, nicastrin, PEN-2 and APH-1 – which must come together for cleavage activity.
Starting from the idea that Alzheimer’s disease might be slowed by inhibiting g-secretase, we have now identified an endogenous inhibitor that prevents gamma-secretase complex assembly and activity and thus might be targeted for therapy (Spasic et al., 2007). Although all four components are present in the ER, their assembly into functional gamma-secretase is somehow restricted. Assembly begins with the binding of nicastrin to APH-1. This binding is competed early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. Rer1p binds to nicastrin, thus interfering with nicastrin’s ability to bind APH-1. Decreasing the amount of Rer1p led to an increase in gamma-secretase activity. Exactly what triggers Rer1p to release nicastrin and allow it to bind to APH-1, and subsequently to the other gamma-secretase components, remains to be determined. Preventing this release might provide a means to reduce gamma-secretase activity and thus amyloid plaque formation.