The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease
Jensen, Anne Mette Gissel (Aarhus University (Dinamarca))
Raska, Jan (International Clinical Research Center. St. Anne's Faculty Hospital Brno)
Fojtik, Petr (International Clinical Research Center. St. Anne's Faculty Hospital Brno)
Monti, Giulia (Aarhus University (Dinamarca))
Lunding, Melanie (Aarhus University (Dinamarca))
Bartova, Simona (Faculty of Medicine (Brno, República Txeca). Department of Histology and Embryology)
Pospisilova, Veronika (Faculty of Medicine (Brno, República Txeca). Department of Histology and Embryology)
van der Lee, Sven J. (Amsterdam UMC. University Medical Center (Països Baixos))
Van Dongen, Jasper (University of Antwerp (Bèlgica))
Bossaerts, Liene (VIB Center for Molecular Neurology (Bèlgica))
Van Broeckhoven, Christine (VIB Center for Molecular Neurology (Bèlgica))
Dols Icardo, Oriol (Institut de Recerca Sant Pau)
Lleó, Alberto (Institut de Recerca Sant Pau)
Bellini, Sonia (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Ghidoni, Roberta (Istituto Centro San Giovanni di Dio Fatebenefratelli)
Hulsman, Marc (Amsterdam UMC. University Medical Center (Països Baixos))
Petsko, Gregory A. (Brigham and Women's Hospital (Boston, Estats Units d'Amèrica))
Sleegers, Kristel (University of Antwerp (Bèlgica))
Bohaciakova, Dasa (International Clinical Research Center. St. Anne's Faculty Hospital Brno (República Txeca))
Holstege, Henne (Amsterdam UMC. University Medical Center (Països Baixos))
Andersen, Olav M. (Aarhus University (Dinamarca))
Universitat Autònoma de Barcelona

Data:	2024
Resum:	Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p. Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p. Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p. Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p. Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p. Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	3Fn-domain ; SORL1-associated Alzheimer's disease ; SORLA ; Dimerization ; Retromer
Publicat a:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 121 Núm. 37 (october 2024) , p. e2408262121, ISSN 1091-6490

DOI: 10.1073/pnas.2408262121
PMID: 39226352

12 p, 3.6 MB

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