title: Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production.
abstract: Mutations in the PSEN1 gene encoding Presenilin-1 (PS1) are the predominant cause of familial Alzheimer's disease (FAD), but the underlying mechanisms remain unresolved. To reconcile the dominant action of pathogenic PSEN1 mutations with evidence that they confer a loss of mutant protein function, we tested the hypothesis that PSEN1 mutations interfere with γ-secretase activity in a dominant-negative manner. Here, we show that pathogenic PSEN1 mutations act in cis to impair mutant PS1 function and act in trans to inhibit wild-type PS1 function. Coexpression of mutant and wild-type PS1 at equal gene dosage in presenilin-deficient mouse embryo fibroblasts resulted in trans-dominant-negative inhibition of wild-type PS1 activity, suppressing γ-secretase-dependent cleavage of APP and Notch. Surprisingly, mutant PS1 could stimulate production of Aβ42 by wild-type PS1 while decreasing its production of Aβ40. Mutant and wild-type PS1 efficiently coimmunoprecipitated, suggesting that mutant PS1 interferes with wild-type PS1 activity via physical interaction. These results support the conclusion that mutant PS1 causes wild-type PS1 to adopt an altered conformation with impaired catalytic activity and substrate specificity. Our findings reveal a novel mechanism of action for pathogenic PSEN1 mutations and suggest that dominant-negative inhibition of presenilin activity plays an important role in FAD pathogenesis.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, MGH-Simches Research Center, Boston, MA 02114, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Heilig
authors.forename: Usha
authors.initials: U
authors.lastname: Gutti
authors.forename: Tara
authors.initials: T
authors.lastname: Tai
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D005799:Genes, Dominant / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053764:Presenilin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases