Endogenous presenilin 1 redistributes to the surface of lamellipodia upon adhesion of Jurkat cells to a collagen matrix

Abstract

Most familial early-onset Alzheimer's disease cases are caused by mutations in the presenilin 1 (PS1) gene. Subcellular localization of the endogenous PS1 is essential for understanding its function, interactions with proteins, and role in Alzheimer's disease. Although numerous studies revealed predominant localization of PS1 to endoplasmic reticulum and Golgi, there are conf licting reports on the localization of PS1 to the cell surface. We found that endogenous PS1 is highly expressed in T lymphocytes (Jurkat cells). Using a variety of methods, we present evidence that endogenous PS1 is localized to the cell surface in addition to intracellular membrane compartments. Moreover, PS1 appeared in high levels on the surface of lamellipodia upon adhesion of the cells to a collagen matrix. The redistribution of PS1 in adhered cells was strikingly similar to that of the well characterized adhesion protein CD44. Cell surface PS1 formed complexes in vivo with actin-binding protein filamin (ABP-280), which is known to form bridges between cell surface receptors and cytoskeleton and mediate cell adhesion and cell motility. Taken together, our results suggest a role of PS1 in cell adhesion and͞or cell-matrix interaction.The presenilin (PS1 and PS2) genes have been identified as major causal genes for early-onset familial Alzheimer's disease (FAD) (1-3). However, the biological functions of presenilins are unknown.The presenilins are integral membrane proteins with a proposed structure of seven to eight hydrophobic transmembrane domains and a hydrophilic loop located between transmembrane domains 6 and 7 (1). More than 60% of amino acid residues in the sequence of PS1 and PS2 are conserved (1, 3). FAD mutations are found throughout the entire molecule of PS1 (4-6).Northern blot analysis and in situ hybridization studies of PS1 and PS2 mRNAs demonstrate a widespread, uniform expression of RNAs both in the brain and peripheral tissues of humans and rodents (1, 7-9). A high level of expression of endogenous presenilins was detected only in neurons (8, 9).Light and electron microscopy studies revealed predominant localization of PS1 and PS2 to endoplasmic reticulum-Golgi compartments and to coated transport vesicles in neurons and in various cell types transfected by PS1 or PS2 cDNAs (9-12). In addition, immunocytochemical studies of transfected cells have identified PS-1 in the nuclear membrane, interphase kinetochores, and centrosomes (13). Conflicting results were reported for localization of PS1 to the plasma membrane (10,(14)(15)(16).PS1 reveals approximately 50% homology with Caenorhabditis elegans protein sel-12 (17), which facilitates signaling mediated by the Notch͞lin-12 family receptors. Notch receptors are cell surface proteins that regulate cell-cell interactions and cell fate choices during T cell and neural development (18,19). The expression of Notch 1 mRNA is decreased significantly in the presomitic mesoderm of PS1 null mice characterized by massive neuronal loss in specific subregions of the mutant br...

The presenilins turned inside out: Implications for their structures and functions

“…1 B and C), strong evidence was obtained that the PS proteins in the cell surface spanned the membrane seven times, with either the 6-TM or 8-TM topographies ruled out. Another subsequent study (16) was consistent with our proposed exoplasmic location of the N-terminal domain of cell-surface PS.…”

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

“…Intriguingly, cellular phenotypes in PIP 2 -compromised cells are reminiscent of those observed in cells expressing FADassociated presenilin mutations, e.g., ion channel and trafficking deficits (15). The potential role of presenilin in PIP 2 metabolism can be further evidenced by occurrence of PS1 in PIP 2 -enriched subcellular compartments, including lipid rafts (44), phagocytic cups (19), lamellipodia (45), and adherent junctions (18). Thus, our study raises the possibility that PIP 2 may play a key role in the multiple cellular defects associated with presenilin FAD mutations.…”

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

“…As alluded to above, PS1 has been localized to almost every membranous compartment of the cell, including ER [26,30,[46][47][48], the Golgi apparatus [26,27,46,49], endosomes [31,50], lysosomes [32], the nuclear envelope [30], mitochondria [33,51], and the plasma membrane [28,[52][53][54][55], including adherens junctions [34,56].…”