Endogenous presenilin-1 targets to endocytic rather than biosynthetic compartments.
Presenilin-1 (PS1), which is linked to familial Alzheimer's disease, participates in the proteolytic processing of Notch and amyloid-beta precursor protein (APP) by an unknown mechanism. Reports of PS1 localization to the endoplasmic reticulum (ER) and Golgi apparatus have focused attention on the early biosynthetic pathway as the site of PS1 function. However, it is unclear how Notch cleavage and APP processing events which occur at or near the cell surface are influenced by PS1. In contrast to some earlier studies, examination of endogenously expressed PS1 in PC12 cells by subcellular fractionation and immunofluorescence microscopy revealed a distribution distinct from that of ER and Golgi markers. Rather, PS1 colocalized with transferrin receptor, a marker for early endosomes. In addition, electron microscopic examination of intact vesicles immunoisolated with PS1 antibodies allowed visualization of endocytic tracer in endosomes. These findings identify an early endosomal pool of PS1 and suggest alternative mechanisms for PS1 interactions with APP and Notch.
Department of Neurology, Emory University School of Medicine, Woodruff Memorial Research Building, Suite 6000, 1639 Pierce Drive, Atlanta, Georgia 30322, USA.
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D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D002451:Cell Compartmentation / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008854:Microscopy, Electron; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D053764:Presenilin-1; D051381:Rats; D051880:Receptors, Notch; D013347:Subcellular Fractions / Q000737:chemistry
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D008565:Membrane Proteins; D053764:Presenilin-1; D051880:Receptors, Notch