The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F24%3A00081782" target="_blank" >RIV/00159816:_____/24:00081782 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14110/24:00137583
Result on the web
<a href="https://www.pnas.org/doi/10.1073/pnas.2408262121" target="_blank" >https://www.pnas.org/doi/10.1073/pnas.2408262121</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1073/pnas.2408262121" target="_blank" >10.1073/pnas.2408262121</a>
Alternative languages
Result language
angličtina
Original language name
The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10700 - Other natural sciences
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
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Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424
e-ISSN
1091-6490
Volume of the periodical
121
Issue of the periodical within the volume
37
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
"e2408262121"
UT code for WoS article
001415698800011
EID of the result in the Scopus database
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