OBJECTIVE: Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. METHODS: We analyzed the genetic associations between AD and 16 SORCS1-single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation. RESULTS: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ. INTERPRETATIONS: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.
OBJECTIVE: Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer's disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that underexpression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. METHODS: We analyzed the genetic associations between AD and 16 SORCS1-single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation. RESULTS: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ. INTERPRETATIONS: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD.
Authors: R Kikuno; T Nagase; K Ishikawa; M Hirosawa; N Miyajima; A Tanaka; H Kotani; N Nomura; O Ohara Journal: DNA Res Date: 1999-06-30 Impact factor: 4.458
Authors: Robert C Green; L Adrienne Cupples; Rodney Go; Kelly S Benke; Timi Edeki; Patrick A Griffith; Mary Williams; Yvonne Hipps; Neill Graff-Radford; David Bachman; Lindsay A Farrer Journal: JAMA Date: 2002-01-16 Impact factor: 56.272
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: Nat Genet Date: 2007-01-14 Impact factor: 38.330
Authors: G Hermey; I B Riedel; M Rezgaoui; U B Westergaard; C Schaller; I Hermans-Borgmeyer Journal: Neurosci Lett Date: 2001-11-02 Impact factor: 3.046
Authors: Aron Marchler-Bauer; John B Anderson; Myra K Derbyshire; Carol DeWeese-Scott; Noreen R Gonzales; Marc Gwadz; Luning Hao; Siqian He; David I Hurwitz; John D Jackson; Zhaoxi Ke; Dmitri Krylov; Christopher J Lanczycki; Cynthia A Liebert; Chunlei Liu; Fu Lu; Shennan Lu; Gabriele H Marchler; Mikhail Mullokandov; James S Song; Narmada Thanki; Roxanne A Yamashita; Jodie J Yin; Dachuan Zhang; Stephen H Bryant Journal: Nucleic Acids Res Date: 2006-11-29 Impact factor: 16.971
Authors: Hao Li; Sally Wetten; Li Li; Pamela L St Jean; Ruchi Upmanyu; Linda Surh; David Hosford; Michael R Barnes; James David Briley; Michael Borrie; Natalie Coletta; Richard Delisle; Daniella Dhalla; Margaret G Ehm; Howard H Feldman; Luis Fornazzari; Serge Gauthier; Neil Goodgame; Danilo Guzman; Sandra Hammond; Paul Hollingworth; Ging-Yuek Hsiung; Joan Johnson; Devon D Kelly; Ron Keren; Andrew Kertesz; Karen S King; Simon Lovestone; Inge Loy-English; Paul M Matthews; Michael J Owen; Mary Plumpton; William Pryse-Phillips; Rab K Prinjha; Jill C Richardson; Ann Saunders; Andrew J Slater; Peter H St George-Hyslop; Sandra W Stinnett; Jina E Swartz; Rachel L Taylor; John Wherrett; Julie Williams; David P Yarnall; Rachel A Gibson; Michael C Irizarry; Lefkos T Middleton; Allen D Roses Journal: Arch Neurol Date: 2007-11-12
Authors: Christopher P Sullivan; Anthony G Jay; Edward C Stack; Maria Pakaluk; Erin Wadlinger; Richard E Fine; John M Wells; Peter J Morin Journal: Neurobiol Dis Date: 2011-04-16 Impact factor: 5.996
Authors: Jeffrey N Savas; Luís F Ribeiro; Keimpe D Wierda; Rebecca Wright; Laura A DeNardo-Wilke; Heather C Rice; Ingrid Chamma; Yi-Zhi Wang; Roland Zemla; Mathieu Lavallée-Adam; Kristel M Vennekens; Matthew L O'Sullivan; Joseph K Antonios; Elizabeth A Hall; Olivier Thoumine; Alan D Attie; John R Yates; Anirvan Ghosh; Joris de Wit Journal: Neuron Date: 2015-08-19 Impact factor: 17.173
Authors: Melkam A Kebede; Angie T Oler; Trillian Gregg; Allison J Balloon; Adam Johnson; Kelly Mitok; Mary Rabaglia; Kathryn Schueler; Donald Stapleton; Candice Thorstenson; Lindsay Wrighton; Brendan J Floyd; Oliver Richards; Summer Raines; Kevin Eliceiri; Nabil G Seidah; Christopher Rhodes; Mark P Keller; Joshua L Coon; Anjon Audhya; Alan D Attie Journal: J Clin Invest Date: 2014-08-26 Impact factor: 14.808