The <i>SORL1</i> p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer’s disease

Truncating genetic variants of <i>SORL1</i>, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in <i>SORL1</i> 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 <i>SORL1</i> 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 <i>SORL1</i> 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-09-03
DOI
https://doi.org/10.1073/pnas.2408262121
Citations
21
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
6.53

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article

The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer’s disease

Petr Fojtík, Marc Hulsman, Gregory A. Petsko, Alberto Lleó et al.
21 citations
Proceedings of the National Academy of Sciences
Alzheimer's disease research and treatments
6.53
article

The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer’s disease

Petr Fojtík, Marc Hulsman, Gregory A. Petsko, Alberto Lleó, Liene Bossaerts, Kristel Sleegers, Giulia Monti, Simona Bártová, Dáša Bohačiaková, Sonia Bellini, Christine Van Broeckhoven, Henne Holstege, Sven J. van der Lee, Roberta Ghidoni, Anne Mette G. Jensen, Olav M. Andersen, Veronika Pospíšilová, Jasper Van Dongen, Oriol Dols‐Icardo, Jan Raška, Melanie Lunding
article en
21 citations

Abstract

Truncating genetic variants of <i>SORL1</i>, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in <i>SORL1</i> 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 <i>SORL1</i> 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 <i>SORL1</i> 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.

Proceedings of the National Academy of SciencesVol. 121(37)
Universitat Autònoma de Barcelona (ES), Brigham and Women's Hospital (US), Harvard University (US), University of Antwerp (BE), Aarhus University (DK), Hospital de Sant Pau (ES), Vlaams Instituut voor Biotechnologie (BE), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Amsterdam Neuroscience (NL), Centro San Giovanni di Dio Fatebenefratelli (IT), VIB-UAntwerp Center for Molecular Neurology (BE), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Vrije Universiteit Amsterdam (NL)
Alzheimer's Association, Health~Holland, Rainwater Charitable Foundation, ZonMw, Novo Nordisk Fonden
Openalex Percentile: Top 3%
Alzheimer's disease research and treatments
6.53
DOIOpen Access PDFOpenAlex
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