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

J 2024

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

JENSEN, Anne Mette G; Jan RAŠKA; Petr FOJTÍK; Giulia MONTI; Melanie LUNDING et al.

Základní údaje

Originální název

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

Autoři

Vydání

Proceedings of the National Academy of Sciences of the United States of America, Washington, National Academy of Sciences, 2024, 0027-8424

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30210 Clinical neurology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 9.100

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/24:00137583

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

Alzheimer’s disease; SORL1 p.Y1816C variant; impaired endosomal dimerization

Štítky

14110517, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 14. 2. 2025 10:25, Mgr. Tereza Miškechová

Anotace

V originále

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.

Návaznosti

LM2018129, projekt VaV

Název: Národní infrastruktura pro biologické a medicínské zobrazování Czech-BioImaging

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, National research infrastructure for biological and medical imaging

LX22NPO5107, projekt VaV

Název: Národní ústav pro neurologický výzkum

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Národní ústav pro neurologický výzkum, 5.1 EXCELES

NU22J-08-00075, projekt VaV

Název: Sledování funkce proteinu SORLA u pacientů s Alzheimerovou chorobou s časným nástupem

Investor: Ministerstvo zdravotnictví ČR, Sledování funkce proteinu SORLA u pacientů s Alzheimerovou chorobou s časným nástupem, Podprogram 2 - juniorský - výzkumníci do 35 let

8F20009, projekt VaV

Název: Identifying and treating SORL1-associated Alzheimer’s disease (Akronym: SORLA - FIX)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Pathogenic SORL1 variants in Alzheimer’s disease, Neurodegenerativní onemocnění (JPND)

Citovat

JENSEN, Anne Mette G; Jan RAŠKA; Petr FOJTÍK; Giulia MONTI; Melanie LUNDING; Simona BÁRTOVÁ; Veronika POSPÍŠILOVÁ; Sven J VAN DER LEE; Jasper Van DONGEN; Liene BOSSAERTS; Christine Van BROECKHOVEN; Oriol DOLS-ICARDO; Alberto LLÉO; Sonia BELLINI; Roberta GHIDONI; Marc HULSMAN; Gregory A PETSKO; Kristel SLEEGERS; Dáša BOHAČIAKOVÁ; Henne HOLSTEGE a Olav M ANDERSEN. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. Washington: National Academy of Sciences, 2024, roč. 121, č. 37, s. 1-12. ISSN 0027-8424. Dostupné z: https://doi.org/10.1073/pnas.2408262121.

@article{2451019,
   author = {Jensen, Anne Mette G and Raška, Jan and Fojtík, Petr and Monti, Giulia and Lunding, Melanie and Bártová, Simona and Pospíšilová, Veronika and van der Lee, Sven J and Dongen, Jasper Van and Bossaerts, Liene and Broeckhoven, Christine Van and DolsandIcardo, Oriol and Lléo, Alberto and Bellini, Sonia and Ghidoni, Roberta and Hulsman, Marc and Petsko, Gregory A and Sleegers, Kristel and Bohačiaková, Dáša and Holstege, Henne and Andersen, Olav M},
   article_location = {Washington},
   article_number = {37},
   doi = {https://doi.org/10.1073/pnas.2408262121},
   keywords = {Alzheimer’s disease; SORL1 p.Y1816C variant; impaired endosomal dimerization},
   language = {eng},
   issn = {0027-8424},
   journal = {Proceedings of the National Academy of Sciences of the United States of America},
   title = {The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease},
   url = {https://www.pnas.org/doi/full/10.1073/pnas.2408262121},
   volume = {121},
   year = {2024}
}

TY  - JOUR
ID  - 2451019
AU  - Jensen, Anne Mette G - Raška, Jan - Fojtík, Petr - Monti, Giulia - Lunding, Melanie - Bártová, Simona - Pospíšilová, Veronika - van der Lee, Sven J - Dongen, Jasper Van - Bossaerts, Liene - Broeckhoven, Christine Van - Dols-Icardo, Oriol - Lléo, Alberto - Bellini, Sonia - Ghidoni, Roberta - Hulsman, Marc - Petsko, Gregory A - Sleegers, Kristel - Bohačiaková, Dáša - Holstege, Henne - Andersen, Olav M
PY  - 2024
TI  - The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease
JF  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 121
IS  - 37
SP  - 1-12
EP  - 1-12
PB  - National Academy of Sciences
SN  - 00278424
KW  - Alzheimer’s disease
KW  - SORL1 p.Y1816C variant
KW  - impaired endosomal dimerization
UR  - https://www.pnas.org/doi/full/10.1073/pnas.2408262121
N2  - 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.
ER  -

JENSEN, Anne Mette G; Jan RAŠKA; Petr FOJTÍK; Giulia MONTI; Melanie LUNDING; Simona BÁRTOVÁ; Veronika POSPÍŠILOVÁ; Sven J VAN DER LEE; Jasper Van DONGEN; Liene BOSSAERTS; Christine Van BROECKHOVEN; Oriol DOLS-ICARDO; Alberto LLÉO; Sonia BELLINI; Roberta GHIDONI; Marc HULSMAN; Gregory A PETSKO; Kristel SLEEGERS; Dáša BOHAČIAKOVÁ; Henne HOLSTEGE a Olav M ANDERSEN. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. \textit{Proceedings of the National Academy of Sciences of the United States of America}. Washington: National Academy of Sciences, 2024, roč.~121, č.~37, s.~1-12. ISSN~0027-8424. Dostupné z: https://doi.org/10.1073/pnas.2408262121.

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