Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria.
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.
Area-Gomez
Estela
E
Department of Neurology, Columbia University Medical Center, New York, New York, USA.
de Groof
Ad J C
AJ
Boldogh
Istvan
I
Bird
Thomas D
TD
Gibson
Gary E
GE
Koehler
Carla M
CM
Yu
Wai Haung
WH
Duff
Karen E
KE
Yaffe
Michael P
MP
Pon
Liza A
LA
Schon
Eric A
EA
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
D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase