Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

NEUROBIOLOGY OF DISEASE

卷:104

Article

Le Guennec, Kilan^1,2  Veugelen, Sarah^3,4  Quenez, Olivier^1,2  Szaruga, Maria^3,4  Rousseau, Stephane^1,2  Nicolas, Gael^1,2  Wallon, David^2,5  Fluchere, Frederique⁶  Frebourg, Thierry⁷  De Strooper, Bart^3,4,8  Campion, Dominique^1,2,9  Chavez-Gutierrez, Lucia^3,4  Rovelet-Lecrux, Anne^1,2 

[1] Normandie Univ, Rouen Univ Hosp, Dept Genet, UNIROUEN,Inserm U1245, F-76000 Rouen, France

[2] Normandie Univ, CNR MAJ, Normandy Ctr Genom & Personalized Med, F-76000 Rouen, France

[3] Univ Leuven, VIB, Ctr Brain & Dis Res, B-3000 Leuven, Belgium

[4] Univ Leuven, Ctr Human Genet, Leuven Res Inst Neurosci & Dis LIND, B-3000 Leuven, Belgium

[5] Normandie Univ, Rouen Univ Hosp, Dept Neurol, UNIROUEN,Inserm U1245, F-76000 Rouen, France

[6] Aix Marseille Univ, AP HM, Dept Neurol & Movement Disorders, Pole Neurosci Clin, Marseille, France

[7] Normandie Univ, Rouen Univ Hosp, Normandy Ctr Genom & Personalized Med, UNIROUEN,Inserm U1245,Dept Genet, F-76000 Rouen, France

[8] UCL, Inst Neurol, Queen Sq, London WC1N 3BG, England

[9] Rouvray Psychiat Hosp, Dept Res, Sotteville Les Rouen, France

关键词: Alzheimer Disease;    Early-onset;    PSEN1;    Hydrophilic loop;    A beta 43;    Amyloid;   

DOI  :  10.1016/j.nbd.2017.04.020

来源: Elsevier

【 摘 要 】

Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56 years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the gamma-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long A beta peptides and enhances the production of A beta 43, which has been shown to be potently amyloidogenic and neurotoxic in vivo. (C)2017 Elsevier Inc. All rights reserved.

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