ArticleActa neuropathologica communications2021
Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease.
Article in Acta neuropathologica communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- The Alzheimer's disease risk gene SORL1 is a regulator of excitatory neuronal function.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Novel Frameshift Variant in SORL1 Gene Identified in a EOAD Family Causes APP Sorting Dysfunction and Endolysosomal Swelling.Molecular neurobiology · 2026Article
- Alzheimer's disease risk single nucleotide polymorphism rs11218343 is linked to functional expression of SORL1 in microglia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- FromCells · 2026Review
- Estradiol ameliorates AD pathology and cognitive deficits by SORLA-mediated APP endosomal trafficking.Alzheimer's research & therapy · 2026Article
- IsmedRxiv : the preprint server for health sciences · 2026Article
- Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.Molecular neurodegeneration · 2025Article
- Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- CRISPR/Cas9 and iPSC-Based Therapeutic Approaches in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2025Review
- Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease.Alzheimer's research & therapy · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- TheProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Functional characterization ofPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Article
- A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.Acta neuropathologica · 2024Article
- Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer.Frontiers in oncology · 2024Article
- A familial missense variant in the Alzheimer's Disease genebioRxiv : the preprint server for biology · 2023Article
- Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.Human genomics · 2023Article
- Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Spatially and temporally distinct patterns of expression for VPS10P domain receptors in human cerebral organoids.Frontiers in cell and developmental biology · 2023Article
- Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons.Frontiers in neuroscience · 2023Article
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
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