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Pathogenic Aß production by heterozygous PSEN1 mutations is intrinsic to the mutant protein and not mediated by conformational hindrance of wild-type PSEN1.
Kurth, Vanessa; Ogorek, Isabella; Münch, Carolina; Lopez-Rios, Javier; Ousson, Solenne; Lehmann, Sandra; Nieweg, Katja; Roebroek, Anton J M; Pietrzik, Claus U; Beher, Dirk; Weggen, Sascha.
Afiliación
  • Kurth V; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
  • Ogorek I; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany; Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Münch C; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
  • Lopez-Rios J; Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Universidad Pablo de Olavide-Junta de Andalucia, Sevilla, Spain.
  • Ousson S; Asceneuron SA, Lausanne, Switzerland.
  • Lehmann S; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
  • Nieweg K; Institute of Pharmacology and Clinical Pharmacy, Philipps-University, Marburg, Germany.
  • Roebroek AJM; Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Pietrzik CU; Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Beher D; Asceneuron SA, Lausanne, Switzerland.
  • Weggen S; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany. Electronic address: sweggen@hhu.de.
J Biol Chem ; 299(8): 104997, 2023 08.
Article en En | MEDLINE | ID: mdl-37394008
Presenilin-1 (PSEN1) is the catalytic subunit of the intramembrane protease γ-secretase and undergoes endoproteolysis during its maturation. Heterozygous mutations in the PSEN1 gene cause early-onset familial Alzheimer's disease (eFAD) and increase the proportion of longer aggregation-prone amyloid-ß peptides (Aß42 and/or Aß43). Previous studies had suggested that PSEN1 mutants might act in a dominant-negative fashion by functional impediment of wild-type PSEN1, but the exact mechanism by which PSEN1 mutants promote pathogenic Aß production remains controversial. Using dual recombinase-mediated cassette exchange (dRMCE), here we generated a panel of isogenic embryonic and neural stem cell lines with heterozygous, endogenous expression of PSEN1 mutations. When catalytically inactive PSEN1 was expressed alongside the wild-type protein, we found the mutant accumulated as a full-length protein, indicating that endoproteolytic cleavage occurred strictly as an intramolecular event. Heterozygous expression of eFAD-causing PSEN1 mutants increased the Aß42/Aß40 ratio. In contrast, catalytically inactive PSEN1 mutants were still incorporated into the γ-secretase complex but failed to change the Aß42/Aß40 ratio. Finally, interaction and enzyme activity assays demonstrated the binding of mutant PSEN1 to other γ-secretase subunits, but no interaction between mutant and wild-type PSEN1 was observed. These results establish that pathogenic Aß production is an intrinsic property of PSEN1 mutants and strongly argue against a dominant-negative effect in which PSEN1 mutants would compromise the catalytic activity of wild-type PSEN1 through conformational effects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: J Biol Chem Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos