Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health
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ABSTRACT:
PROVIDER: PRJNA925533 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23126510.fastq.gz | Fastqsanger.gz | |||
| SRR23126511.fastq.gz | Fastqsanger.gz | |||
| SRR23126512.fastq.gz | Fastqsanger.gz | |||
| SRR23126513.fastq.gz | Fastqsanger.gz | |||
| SRR23126514.fastq.gz | Fastqsanger.gz |
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Project description:Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson’s and Alzheimer’s diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform the first integrated multiomics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify profound changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide an unprecedented integrated view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
2023-04-17 | GSE223292 | GEO
Project description:Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling late-stage maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson’s and Alzheimer’s diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform the first integrated multiomics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify profound changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide an unprecedented integrated view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
2023-07-20 | PXD041323 | Pride
Project description:Retromer controls cellular homeostasis through regulating integral membrane protein sorting and transport and by controlling maturation of the endo-lysosomal network. Retromer dysfunction, which is linked to neurodegenerative disorders including Parkinson's and Alzheimer's diseases, manifests in complex cellular phenotypes, though the precise nature of this dysfunction, and its relation to neurodegeneration, remain unclear. Here, we perform an integrated multi-omics approach to provide precise insight into the impact of Retromer dysfunction on endo-lysosomal health and homeostasis within a human neuroglioma cell model. We quantify widespread changes to the lysosomal proteome, indicative of broad lysosomal dysfunction and inefficient autophagic lysosome reformation, coupled with a reconfigured cell surface proteome and secretome reflective of increased lysosomal exocytosis. Through this global proteomic approach and parallel transcriptomic analysis, we provide a holistic view of Retromer function in regulating lysosomal homeostasis and emphasise its role in neuroprotection.
| S-EPMC10227043 | biostudies-literature
Project description:Synaptic dysfunction is an early hallmark of Alzheimer’s disease, characterized by the disruption of synaptic transmission and plasticity. Central to these processes is endosomal trafficking, mediated by the retromer complex, which orchestrates the movement of vesicle contents for recycling to the plasma membrane, return to the Golgi, or degradation. Variants of VPS35, the cargo recognition component of the retromer complex, have been linked to neurodegenerative diseases, including Parkinson’s disease (PARK17, D620N mutation) and Alzheimer’s disease (L625P mutation). While substantial research has focused on Parkinson's, the role of VPS35 in Alzheimer’s has been less explored. This study investigates the acute neuroprotective effects of retromer-stabilizing compounds in the 5xFAD mouse model of Alzheimer’s. Our results reveal that stabilization of the retromer complex not only mitigates pathogenic Aβ production mechanisms but also compensates for early synaptic dysfunction and microglial activation. Specifically, we observed significant modulation of genes involved in long-term potentiation and a reduction in abnormal retromer-associated cargos. These findings highlight the potential of retromer stabilisation as atherapeutic strategy to address fundamental pathological pathological processes in Alzheimer's disease.
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Project description:The mu opioid receptor (MOR) is protected from opioid-induced trafficking to lysosomes and proteolytic downregulation by its ability to access the endosomal recycling pathway through its C-terminal recycling motif, LENL. MOR sorting towards the lysosome results in downregulation of opioid signaling while recycling of MOR to the plasma membrane preserves signaling function. However, the mechanisms by which LENL promotes MOR recycling are unknown, and this sequence does not match any known consensus recycling motif. Here we took a functional genomics approach with a comparative genome-wide screen design to identify genes which control opioid receptor expression and downregulation. We identified 146 hits including all three subunits of the endosomal Retromer complex. We show that the LENL motif in MOR is a novel Retromer recycling motif and that LENL is a necessary, sufficient, and conserved mechanism to give MOR access to the Retromer recycling pathway and protect MOR from agonist-induced downregulation to multiple clinically relevant opioids including fentanyl and methadone.
2026-02-17 | GSE283358 | GEO
Project description:Lysosomal Downregulation of the Mu Opioid Receptor is Opposed by the Retromer Complex
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Project description:The D620N VPS35 mutation disrupts retrograde endosome to Golgi retromer Trafficking. Thus causes lysosome dysfunction, enhances LRRK2 kinase activity and leads to Parkinson’s disease. We employed a LysoTag immunoprecipitation approach to assess how this impacts lysosomes using quantitative proteomics. The VPS35[D620N] mutation alters the expression of over 350 lysosomal proteins, and induces recruitment of LRRK2 phosphorylated Rab proteins to the lysosome, as well as the phosphoRab effector protein RILPL1.
2023-11-28 | PXD042502 | Pride
Project description:Efficient clearance of dead cells, termed efferocytosis, is essential for maintaining tissue homeostasis. Although the cellular and molecular mechanisms regulating apoptotic cell (AC) internalization are well established, our understanding of AC digestion upon engulfment remains elusive. Here, we show that the retromer subunits are recruited to AC-containing phagosomes during efferocytosis and promote AC corpse degradation. Mechanistically, retromer stabilizes NOX2, a key regulator for LC3 recruitment to AC-containing phagosomes, leading to the maturation of phagolysosomes and corpse degradation. Meanwhile, TBC1D5, a binding partner for both retromer and LC3, also accelerates phagolysosomal maturation and AC degradation. Hence, our study indicates that retromer promotes LC3 recruitment and phagolysosomal maturation through stabilizing NOX2 and interacting with TBC1D5. This work elucidates a novel role of retromer in AC degradation and suggests a new avenue to explore the potential of retromer-stabilizing strategies to restore efficient AC clearance in disease.
2025-11-25 | GSE310776 | GEO
Project description:Endo-lysosomal compartments exchange proteins by fusing, fissioning, and through endosomal transport carriers. Thereby, they sort many plasma membrane receptors and transporters and control cellular signaling and metabolism. How the membrane fission events are catalyzed is poorly understood. Here, we identify the novel CROP complex as a factor acting at this step. CROP integrates PROPPIN Atg18 with a part of the endosome- and vacuole-associated retromer complex to generate a membrane fission device of much higher potency. We studied its activity in yeast, in human cells and on liposomes.
2022-05-05 | PXD031244 | Pride
Project description:Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, Desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides the first evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.
2023-07-24 | PXD036646 | Pride