title: Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1-/- phenotype and forms complexes with wildtype PS1 and nicastrin.
abstract: The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer's disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1(∆exon8)). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1(∆exon8) reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1(∆exon8) did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1(∆exon8) is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1(∆exon8) in vivo by crossing PS1(∆exon8) transgenics with either PS1-null or Dutch APP(E693Q) mice. As a control, we crossed APP(E693Q) with mice expressing a deletion in an adjacent exon (PS1(∆exon9)). PS1(∆exon8) did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1(∆exon8) interacts with nicastrin, participating in the γ-secretase complex formation. These data support that catalytically inactive PS1(∆exon8) is generated physiologically and participates in protein-protein interactions.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Hannah
authors.initials: H
authors.lastname: Brautigam
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Cesar L
authors.initials: CL
authors.lastname: Moreno
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Cellular and Molecular Medicine,University of California San Diego, La Jolla, CA 92037.|Department of Preclinical Biology, OrPhi Therapeutics, Carlsbad, CA 92008.
authors.forename: John W
authors.initials: JW
authors.lastname: Steele
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, PA 19104.
authors.forename: Alexey
authors.initials: A
authors.lastname: Bogush
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Dickstein
authors.affiliation: Neuroscience Research Australia, Sydney, NSW 2031, Australia.|School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.affiliation: Neuroscience Research Australia, Sydney, NSW 2031, Australia.|School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, IL 60637.
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY 10016.|Nathan Kline Institute Center for Dementia Research, Orangeburg, NY 10962.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|James J. Peters VA Medical Center, Bronx, NY 10468.
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005453:Fluorescence; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018345:Mice, Knockout; D009043:Motor Activity; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017384:Sequence Deletion / Q000235:genetics; D019076:Transgenes
chemical_list: D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D053764:Presenilin-1; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases