Transcriptome analysis of a protein-truncating mutation in sortilin-related receptor 1 (sorl1) associated with early-onset familial Alzheimer's disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains
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ABSTRACT:
PROVIDER: PRJNA656952 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12446284_1.fastq.gz | Fastqsanger.gz | |||
| SRR12446284_2.fastq.gz | Fastqsanger.gz | |||
| SRR12446285_1.fastq.gz | Fastqsanger.gz | |||
| SRR12446285_2.fastq.gz | Fastqsanger.gz | |||
| SRR12446286_1.fastq.gz | Fastqsanger.gz |
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Project description:The early cellular stresses which eventually lead to Alzheimer’s disease (AD) remain poorly understood. This is because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes likely indicating changes in mitochondrial and ribosomal function.
2021-01-11 | GSE156167 | GEO
Project description:Coding mutations in SORL1, the gene encoding sortilin-related receptor with A-type repeats (SORLA) are common in individuals suffering from Alzheimer’s disease (AD) of unknown etiology. These findings suggest SORL1 as a novel familial disease gene causative of AD. SORL1 mutations characterized so far have mainly been shown to impact folding and maturation of the receptor polypeptide. While these previous findings support the relevance of SORLA dysfunction for AD pathology, they provide little information about activity of this intracellular sorting receptor crucial for aging brain health. Here, we have characterized the N1358S variant of SORLA, carrying a mutation in a major ligand binding domain of the receptor. Using unbiased interactome studies, we show that N1358S impacts the ability of SORLA to interact with proteins involved in formation and release of extracellular vesicle (EVs) from cells. Consequently, expression of SORLAN1358S in iPSC-derived human microglia impairs their ability to produce trophic EVs that support maturation of neurons, a defect also seen in microglia lacking the receptor. Our findings document a unique role for SORLA in microglia to neuron crosstalk through EVs, and suggest loss of neurotrophic support in the brain of SORL1N1358S carriers.
2025-09-15 | PXD061828 | Pride
Project description:To prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains, comparing wild type fish with their siblings heterozygous for EOfAD-like or putatively loss-of-function mutations in sorl1, or transheterozygous for these mutations. Differential gene expression analysis identified a small number of differentially expressed genes due to the sorl1 genotypes. We also performed enrichment analysis on all detectable genes to obtain a more complete view on changes to gene expression by performing three methods of gene set enrichment analysis, then calculated an overall significance value using the harmonic mean p-value. This identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.
2020-10-22 | GSE151999 | GEO
Project description:SORL1 (Sortilin-Related Receptor 1) is a key player in endosomal trafficking and has been implicated in neurodegenerative disorders. To identify SORL1 binding partners, we performed immunoprecipitation (IP) of SORL1, followed by mass spectrometry-based proteomic analysis. THP-1 cell lysates were used as the source material for immunoprecipitation, and IgG controls were included to filter out non-specific interactions. The resulting datasets provide insights into SORL1-associated protein complexes, offering potential targets for further functional studies.
2026-04-13 | PXD061057 | Pride
Project description:Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell derived neurons (hiPSC-Ns) to test this hypothesis. In SORL1 deficient (SORL1KO) cell lines, we map the trafficking of the glutamate receptor and the BDNF neurotrophic receptor, two kinds of transmembrane proteins that depend on endosomal recycling and that are linked to AD pathophysiology. We find that as with APP, SORL1 is required for efficient endosomal recycling of the glutamate receptor AMPA1 (GLUA1) and the BDNF receptor Tropomyosin-related kinase B (TRKB). Next, we used cell lines engineered to overexpress SORL1 and find that increased SORL1 expression enhances recycling for APP and GLUA1. Finally, we performed an unbiased transcriptomic screen of SORL1KO neurons and the data further support SORL1’s role in endosomal recycling. We observed altered expression networks that regulate cell surface trafficking and neurotrophic signaling. Collectively, and together with other recent observations, these findings suggest that SORL1 is a key and broad regulator of retromer-dependent endosomal recycling in neurons, a conclusion that has both pathogenic and therapeutic implications.
2022-03-01 | GSE180793 | GEO
Project description:SORL1 is implicated in the pathogenesis of Alzheimer’s disease (AD) through genetic studies. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs are differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in APOE and CLU and altered lipid profiles. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1 null neurons but does not rescue APOE levels. Pathway analyses implicate TGF-β/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in post-mortem brain. These studies provide a mechanistic link between strong genetic risk factors for AD.
2023-10-24 | PXD044093 | Pride
Project description:Sortilin is a ubiquitous membrane receptor mediating protein trafficking along different cellular routes. In the thyroid gland, sortilin was proposed as a post-endocytic receptor of the thyroid hormone precursor, thyroglobulin (TG). It was reported that sortilin preferably shuttles iodinated TG to the lysosome, thereby facilitating the proteolytic release of thyroid hormones. However, the molecular details of this interaction are unknown. In this work, using an integrative approach, we reveal the structural basis of human TG recognition by sortilin. We found that sortilin interacts with a TG C-terminal peptide, which is more exposed in the monomeric TG than in its commonly found dimeric form. Unlike previously hypothesised, we suggest that the TG iodination state does not affect interaction with sortilin, which could act as a scavenger for degraded TG, as proposed for other cargoes. By comparing the mode of binding of TG and other known sortilin partners, we then derived a consensus ligand recognition motif. Overall, this study broadens understanding on the role of sortilin in TG trafficking and provides insight into general signatures for sortilin cargoes in other tissues.
2026-01-27 | PXD062462 | Pride
Project description:SORL1 is strongly implicated in the pathogenesis of Alzheimer’s disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE and CLU levels, an increase in the accumulation of lipid droplets and altered lipid profiles. Pathway analysis implicated intracellular transport pathways and TGF-β/SMAD signaling in the function of SORL1 in neurons. Enhancement of retromer-mediated trafficking and autophagy rescued tau phenotypes observed in SORL1 null neurons but did not rescue APOE levels. However, stimulation and inhibition of SMAD signaling in neurons modulated APOE RNA levels in a SORL1-dependent manner. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.
2023-07-24 | GSE238013 | GEO
Project description:This study investigates the transcriptomic response of wild-type (WT) and SORL1 knockout (KO) iPSC-derived microglia following treatment. For microglia differentiation protocol please see PMID: 38600587. Bulk RNA sequencing was performed to assess gene expression changes induced by a 48-hour treatment with 10 ng/ml of IFN-γ. The study aims to explore the role of SORL1 in microglial function and its potential impact on neuroinflammatory or neurodegenerative pathways. Differential gene expression analysis will help identify pathways regulated by SORL1 deficiency in response to external stimuli.
2026-02-17 | GSE289806 | GEO
Project description:RBM20 is a cardiac splicing factor responsible for splicing of several cardiac genes such as TTN, TRDN, RyR2, PDLIM1, and CAMK2D. Mutations in RBM20 are a major cause of familial dilated cardiomyopathy (DCM), and lead to missplicing of RBM20 target genes. Here, we describe a novel pathogenic truncating mutation, RBM20 c.1222dupC, identified in a patient with mitral valve prolapse and late onset familial DCM. This mutation introduces a premature termination codon and generates a truncated protein of ~55 kDa in vitro. Splicing assays demonstrated complete loss of activity and no dominant-negative effect on WT RBM20. Overexpression in NRCMs revealed that the truncated protein localized to both cytoplasm and nucleus, partially co-localizing with WT RBM20, despite lacking the RS and RRM domains. To model the patient’s condition, we generated heterozygous c.1222dupC iPSC-derived cardiomyocytes. Western blot analysis of endogenous RBM20 revealed a strong reduction in RBM20 protein level. RT-PCR revealed splicing defects in canonical RBM20 targets, and RNA-sequencing identified widespread splicing abnormalities, including in established RBM20 targets (TTN, RyR2, CAMK2D, and CACNA1G). Together, these findings establish RBM20 c.1222dupC as a pathogenic truncating variant that causes DCM primarily through haploinsufficiency.
2026-03-18 | GSE308500 | GEO