Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease
- PMID: 23813966
- DOI: 10.1242/jcs.125393
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.
Keywords: APP; Alzheimer disease; Protein transport; Retromer; VPS10-domain receptors.
Similar articles
-
Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain.J Neurosci. 2015 Sep 16;35(37):12703-13. doi: 10.1523/JNEUROSCI.0427-15.2015. J Neurosci. 2015. PMID: 26377460 Free PMC article.
-
Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. doi: 10.1073/pnas.0503689102. Epub 2005 Sep 7. Proc Natl Acad Sci U S A. 2005. PMID: 16174740 Free PMC article.
-
LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease.Mol Neurodegener. 2012 Jun 26;7:31. doi: 10.1186/1750-1326-7-31. Mol Neurodegener. 2012. PMID: 22734645 Free PMC article.
-
The Role of SORL1 in Alzheimer's Disease.Mol Neurobiol. 2015;51(3):909-18. doi: 10.1007/s12035-014-8742-5. Epub 2014 May 16. Mol Neurobiol. 2015. PMID: 24833601 Review.
-
Retromers in Alzheimer's disease.Neurodegener Dis. 2012;10(1-4):116-21. doi: 10.1159/000335910. Epub 2012 Mar 3. Neurodegener Dis. 2012. PMID: 22398391 Review.
Cited by
-
Risk factor SORL1: from genetic association to functional validation in Alzheimer's disease.Acta Neuropathol. 2016 Nov;132(5):653-665. doi: 10.1007/s00401-016-1615-4. Epub 2016 Sep 16. Acta Neuropathol. 2016. PMID: 27638701 Free PMC article. Review.
-
Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models.Transl Neurodegener. 2019 Dec 5;8:35. doi: 10.1186/s40035-019-0176-6. eCollection 2019. Transl Neurodegener. 2019. PMID: 31827783 Free PMC article.
-
Molecular mechanisms underlying actions of certain long noncoding RNAs in Alzheimer's disease.Metab Brain Dis. 2020 Jun;35(5):681-693. doi: 10.1007/s11011-020-00564-9. Epub 2020 Mar 17. Metab Brain Dis. 2020. PMID: 32185592 Review.
-
The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression.Cells. 2023 Apr 21;12(8):1204. doi: 10.3390/cells12081204. Cells. 2023. PMID: 37190113 Free PMC article. Review.
-
Conventional and Unconventional Protein Secretion in Yeast and Animal Cells.Methods Mol Biol. 2024;2841:1-17. doi: 10.1007/978-1-0716-4059-3_1. Methods Mol Biol. 2024. PMID: 39115761 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
