title: SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.
abstract: Proteolytic generation of amyloidogenic amyloid β (Aβ) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the γ-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTFα) in a SORLA-dependent manner. SORLA-mediated Aβ reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface.
  
  
  
  Many genes have been identified as risk factors for Alzheimer's disease (AD), and a large proportion of these genes function to limit production or toxicity of the AD-associated amyloid β (Aβ) peptide. Whether and how these genes precisely operate to limit AD onset remains an important question. We identify binding and trafficking interactions between two of these factors, SORLA and SNX27, and demonstrate that SNX27 can direct trafficking of SORLA and the Aβ precursor APP to the cell surface to limit the production of Aβ. Diversion APP to the cell surface through modulation of this molecular complex may represent a complimentary strategy for future development in AD treatment.
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Timothy Y
authors.initials: TY
authors.lastname: Huang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: I-Chu
authors.initials: IC
authors.lastname: Tseng
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Robert
authors.initials: R
authors.lastname: Thompson
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany, and.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, xuh@sbpdiscovery.org.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000682:Amyloid / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D011973:Receptors, LDL / Q000378:metabolism*; D058305:Sorting Nexins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C500393:Snx27 protein, mouse; C491168:Sorl1 protein, mouse; D058305:Sorting Nexins
keywords: APP; Alzheimer's disease; SNX27; SORLA; endosome recycling; protein trafficking