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

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 PinessiInnocenzo 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

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765 Scopus citations

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 Β peptide (AΒ) 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 AΒ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)168-177
Number of pages10
JournalNature genetics
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Genetics

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    Rogaeva, E., Meng, Y., Lee, J. H., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C. T., Cheng, R., Hasegawa, H., Chen, F., Shibata, N., Lunetta, K. L., Pardossi-Piquard, R., Bohm, C., Wakutani, Y., Cupples, L. A., Cuenco, K. T., Green, R. C., ... St. George-Hyslop, P. (2007). The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature genetics, 39(2), 168-177. https://doi.org/10.1038/ng1943