SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1
Open accessAbstract
SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid beta-peptide formation.
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LR11/SorLA sequesters APP in the trans-Golgi network, decreasing the amount of APP in post-Golgi compartments and the plasma membrane.
“LR11/SorLA sequesters APP in the trans-Golgi network, decreasing the amount of APP in post-Golgi compartments and the plasma membrane (Andersen et al., 2005; Schmidt et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Schmidt et al., 2007
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Andersen, O. M., Schmidt, V., Spoelgen, R., Gliemann, J., Behlke, J., Galatis, D., McKinstry, W. J., Parker, M. W., Masters, C. L., Hyman, B. T., et al. (2006) · Biochemistry · doi:10.1021/bi052120v · Cited by 178 · see citing works
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- Andersen, O. M., Reiche, J., Schmidt, V., Gotthardt, M., Spoelgen, R., Behlke, J., von Arnim, C. A., Breiderhoff, T., Jansen, P., Wu, X., Bales, K. R., Cappai, R., Masters, C. L., Gliemann, J., Mufson, E. J., Hyman, B. T., Paul, S. M., Nykjaer, A., and Willnow, T. E. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 13461-13466
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The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
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- Authors
- Schmidt, V., Sporbert, A., Rohe, M., Reimer, T., Rehm, A., Andersen, O. M., & Willnow, T. E.
- Affiliations
- Max Delbrück Center (DE)
- Corresponding author
- Willnow, Thomas E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 282
- Issue
- 45
- Pages
- 32956-32964
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2068688599
- Cited by
- 181
- References
- 3
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 13 · 2014: 15 · 2013: 7 · 2012: 15
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- American Health Assistance Foundation
- Sundhed og Sygdom, Det Frie Forskningsråd
- Alzheimer Forschung Initiative
- Deutsche Forschungsgemeinschaft
- Lundbeckfonden
- H. Lundbeck A/S
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SorLA, LR11, amyloid precursor protein, APP processing, generalized gradient approximation, adaptor proteins, trans-Golgi network, protein trafficking, Alzheimer's disease, amyloid-beta, amyloidogenic processing
- MeSH terms
- Animals, Cell Line, Cell Survival, Endoplasmic Reticulum, Glycosylation, Humans, Mutation, Protein Binding, Amyloid beta-Protein Precursor, ADP-Ribosylation Factors, Protein Transport, LDL-Receptor Related Proteins, Membrane Transport Proteins, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport
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