Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease
Abstract
Excessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid β peptides (Aβ) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.
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SORL1 underexpression is associated with an increase in Aβ production by blocking redirection of endocytosed APP to the trans-Golgi network.
“SORL1 underexpression has also been associated with an increase in Aβ production by blocking the redirection of endocytosed APP to the trans-Golgi network, which reduces APP processing in endosomes [113, 144, 152].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [144]
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The Role of SORL1 in Alzheimer’s Disease
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- Authors
- Willnow, T. E., & Andersen, O. M.
- Affiliations
- Max Delbrück Center (DE)
- Aarhus University (DK)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2013-01-01
- Volume
- 126
- Issue
- Pt 13
- Pages
- 2751-60
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2099492825
- Cited by
- 121
- References
- 12
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 2
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF11OC1015311)
- 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 › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- SorLA, amyloid precursor protein, Alzheimer's disease, APP trafficking, amyloid-beta, secretases, trans-Golgi network, early endosomes, anterograde transport, retrograde transport, endocytosis, neurodegeneration
- MeSH terms
- Alzheimer Disease, Brain, Cell Membrane, Cell Movement, Gene Expression Regulation, Humans, Neurons, Endosomes, Signal Transduction, Amyloid beta-Protein Precursor, Protein Transport, trans-Golgi Network, LDL-Receptor Related Proteins, Membrane Transport Proteins, Amyloid Precursor Protein Secretases, Proteolysis
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