Multiple roles for presenilins demonstrated by characterization of presenilin null cells

Presenilins (PSs) are a family of multi-transmembrane proteins identified by dominant gain-of-function mutations involved in early-onset Alzheimer\u27s disease. The normal biology of these proteins has been the topic of much investigation, as PSs appear to be involved in multiple varied cellular events. PSs are required for the transmembrane proteolysis of multiple proteins, including the amyloid precursor protein (APP) and the developmental protein Notch, and bear characteristics to suggest they are aspartyl proteases directly responsible for the cleavage of these proteins. However, PSs have also been linked to a number of functions which do not appear to involve protein cleavage, including the regulation of proteins within the wingless/wnt signal transduction pathway, stabilization of cadherin-dependent cell adhesion junctions, controlling the influx of calcium into intracellular stores, and the promotion of apoptosis. Here, the understanding of PS function was expanded by examination of neurons and fibroblasts derived from PS knockout (−/−) mice. Although the role of PSs in the cleavage of APP has been well characterized, careful examination of γ-secretase cleavage in several intracellular organelles in these cells demonstrated that PS involvement in APP proteolysis is organelle-specific. Whereas PSs appear to be required for γ-secretase activity in the Golgi apparatus and downstream organelles, a PS-independent γ-secretase resides in the endoplasmic reticulum (ER) and is fully active in PS −/− cells. Further, a novel phenotype associated with PS1 −/− cells involving degradative organelles was also identified and characterized. In PS1 −/− neurons and fibroblasts, there is a significant accumulation of enlarged lysosomal organelles, which appears to be governed by dysregulation of intracellular calcium stores. Further, the appearance of these organelles is accompanied by a selective association of α- and β-synuclein proteins, suggesting a role for these proteins in the function of the organelles. These observations of a novel γ-secretase in the ER and a proliferation of degradative organelles with which synucleins interact not only have implications for the understanding of PS function, but may also highlight early events in both AD and synuclein-related disorders, respectively