title: Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria.
abstract: Presenilin-1 (PS1) and -2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, gamma-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
authors.forename: Ad J C
authors.initials: AJ
authors.lastname: de Groof
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
authors.forename: Wai Haung
authors.initials: WH
authors.lastname: Yu
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duff
authors.forename: Michael P
authors.initials: MP
authors.lastname: Yaffe
authors.forename: Liza A
authors.initials: LA
authors.lastname: Pon
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003066:Coenzyme A Ligases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase