The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

Abstract

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.

• Authors: Ekaterina Rogaeva, Yan Meng, Joseph H Lee, Yongjun Gu, Toshitaka Kawarai, Fanggeng Zou, Taiichi Katayama, Clinton T Baldwin, Rong Cheng, Hiroshi Hasegawa, Fusheng Chen, Nobuto Shibata, Kathryn L Lunetta, Raphaelle Pardossi-Piquard, Christopher Bohm, Yosuke Wakutani, L Adrienne Cupples, Karen T Cuenco, Robert C Green, Lorenzo Pinessi, Innocenzo Rainero, Sandro Sorbi, Amalia Bruni, Ranjan Duara, Robert P Friedland, Rivka Inzelberg, Wolfgang Hampe, Hideaki Bujo, You-Qiang Song, Olav M Andersen, Thomas E Willnow, Neill Graff-Radford, Ronald C Petersen, Dennis Dickson, Sandy D Der, Paul E Fraser, Gerold Schmitt-Ulms, Steven Younkin, Richard Mayeux, Lindsay A Farrer, Peter St George-Hyslop
• Journal: Nature genetics (Nat Genet) Vol. 39 Issue 2 Pg. 168-77 (Feb 2007) ISSN: 1061-4036 [Print] United States
• PMID: 17220890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• LDL-Receptor Related Proteins
• Membrane Transport Proteins
• Protease Nexins
• Receptors, Cell Surface
• SORL1 protein, human
• VPS35 protein, human
• Vesicular Transport Proteins

Topics

• Age of Onset
• Alzheimer Disease (genetics)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Cell Line
• Endosomes (metabolism)
• Genetic Variation
• Haplotypes
• Humans
• Introns
• LDL-Receptor Related Proteins (genetics)
• Membrane Transport Proteins (genetics)
• Models, Genetic
• Organ Specificity
• Polymorphism, Single Nucleotide
• Protease Nexins
• Receptors, Cell Surface (metabolism)
• Vesicular Transport Proteins (metabolism)