The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.
Rogaeva
Ekaterina
E
Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada.
Meng
Yan
Y
Lee
Joseph H
JH
Gu
Yongjun
Y
Kawarai
Toshitaka
T
Zou
Fanggeng
F
Katayama
Taiichi
T
Baldwin
Clinton T
CT
Cheng
Rong
R
Hasegawa
Hiroshi
H
Chen
Fusheng
F
Shibata
Nobuto
N
Lunetta
Kathryn L
KL
Pardossi-Piquard
Raphaelle
R
Bohm
Christopher
C
Wakutani
Yosuke
Y
Cupples
L Adrienne
LA
Cuenco
Karen T
KT
Green
Robert C
RC
Pinessi
Lorenzo
L
Rainero
Innocenzo
I
Sorbi
Sandro
S
Bruni
Amalia
A
Duara
Ranjan
R
Friedland
Robert P
RP
Inzelberg
Rivka
R
Hampe
Wolfgang
W
Bujo
Hideaki
H
Song
You-Qiang
YQ
Andersen
Olav M
OM
Willnow
Thomas E
TE
Graff-Radford
Neill
N
Petersen
Ronald C
RC
Dickson
Dennis
D
Der
Sandy D
SD
Fraser
Paul E
PE
Schmitt-Ulms
Gerold
G
Younkin
Steven
S
Mayeux
Richard
R
Farrer
Lindsay A
LA
St George-Hyslop
Peter
P
D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007438:Introns; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008957:Models, Genetic; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C102582:SORL1 protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins