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SORLA regulates calpain‐dependent degradation of synapsin
Abstract
Introduction: Sorting‐related receptor with A‐type repeats (SORLA) is an intracellular sorting receptor in neurons and a major risk factor for Alzheimer disease. Methods: Here, we performed global proteome analyses in the brain of SORLA‐deficient mice followed by biochemical and histopathologic studies to identify novel neuronal pathways affected by receptor dysfunction. Results: We demonstrate that the lack of SORLA results in accumulation of phosphorylated synapsins in cortex and hippocampus. We propose an underlying molecular mechanism by demonstrating that SORLA interacts with phosphorylated synapsins through 14‐3‐3 adaptor proteins to deliver synapsins to calpain‐mediated proteolytic degradation. Discussion: Our results suggest a novel function for SORLA which is in control of synapsin degradation, potentially impacting on synaptic vesicle endocytosis and/or exocytosis.
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SORLA has been previously shown to regulate and traffic neuronal components, including sorting/trafficking the GDNF/GFRa1 complex, regulating calpain-dependent degradation of synapsin, and trafficking glutamate receptors such as GLUA1.
“Indeed, SORLA has been previously regulate and traffic neuronal components, including sorting/trafficking the GDNF/GFRa1 complex (Glerup, Lume et al. 2013), regulating calpain-dependent degradation of synapsin (Hartl, Nebrich et al. 2016), and trafficking glutamate receptors such as GLUA1 (Mishra, Knupp et al. 2022), which could consequently affect neurodegenerative outcome.”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Hartl, Nebrich et al. 2016
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SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain
Huang, H., Shi, C. H., Yang, W., Piña-Crespo, J. C., Bhatnagar, J., Curatolo, J., Murad, R., Shah, P., Campos, A., Houser, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.aed6825 · Cited by 1
Metadata
- Authors
- Hartl, D., Nebrich, G., Klein, O., Stephanowitz, H., Krause, E., & Rohe, M.
- Affiliations
- Institute for Medical Genetics and Human Genetics Charité–University Medicine Berlin Germany
- Leibniz Institute for Molecular Pharmacology Berlin Germany
- Max-Delbrueck-Center for Molecular Medicine Berlin Germany
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-03-25
- Volume
- 12
- Issue
- 9
- Pages
- 952-963
- ISSN
- 1552-5260
- 1552-5279
- Cited by
- 14
- References
- 4
- Language
- en
- Funders
- American Health Assistance Foundation (A2011601)
- Deutsche Forschungsgemeinschaft (HA6155/1‐1, HA6155/1‐2)
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