Small molecule targets TMED9, promotes lysosomal degradation to reverse proteinopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA533310 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8921490_1.fastq.gz | Fastqsanger.gz | |||
| SRR8921490_2.fastq.gz | Fastqsanger.gz | |||
| SRR8921500_1.fastq.gz | Fastqsanger.gz | |||
| SRR8921500_2.fastq.gz | Fastqsanger.gz | |||
| SRR8921510_1.fastq.gz | Fastqsanger.gz |
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Project description:Herein, we develop a novel lysosome-localizable reactive diazirine molecule MDA and demonstrate its enhanced labeling capability in lysosomal microenvironment. Further, we develop a novel microenvironment-specific enrichment (MiSE) strategy for profiling lysosomal proteome, containing MDA-based labeling and affinity enrichment. We demonstrate the effectiveness of MiSE in profiling the lysosomal proteome of living SH-SY5Y cells, identifying 1651 lysosomal proteome, including 126 lysosome-annotated proteins. Furthermore, we utilize MiSE coupled with data-independent acquisition (DIA) analysis to investigate the dynamic changes in the lysosomal proteome in SH-SY5Y cells upon ubiquitin-proteasome system (UPS) inhibition using four proteasome inhibitors. Our results reveal 117 UPS-inhibition related lysosomal proteins, highlighting their involvement in stress response and cell cycle regulation. Notably, we observe distinct proteomic signatures for each inhibitor, suggesting the unique mechanisms of lysosomal response to UPS inhibition.
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Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to the eventual death of motor neurons. Described cases of familial ALS have emerged the significance of protein misfolding and aggregation of two functionally related proteins, FUS and TDP-43, implicated in RNA metabolism. Herein, using the in vivo model of FUS-mediated proteinopathy (FUS1-359 mice) we performed the comprehensive analysis encompassing the onset of the first clinical symptoms, inclusions formations as well as changes in gene expression profile in motor neurons and surrounding microglia. The obtained data show that FUS-mediated proteinopathy is predominantly asymptomatic in terms of both the clinical symptoms and molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). From this time point the pathological process develops very rapidly resulting in massive FUS-positive inclusions formation which is accompanying by the transcriptional “burst” in the spinal cord cells. Specifically it manifests in activation of pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. We conclude that a stable course of the pathological process, as well as described accompanying features, make FUS1-359 mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.
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Project description:Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases, which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher’s disease, characterized by <15% of normal glucocerebrosidase function, is the most common lysosomal storage disease and is a prominent risk factor for developing Parkinson’s disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, discovered from a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient–derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An ISR antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because integrated stress response (ISR) signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed, This strategy of combining a PIKfyve modulator with an integrated stress response inhibitor improves mutant lysosomal hydrolase function in cellular models of additional lysosomal storage diseases.
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Project description:Blunted first-phase insulin secretion and insulin deficiency are indicators of β-cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β-cell function. Here, we identify the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)-β-cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC-β-cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localises to clathrin-coated vesicles (CCVs) close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody (mAB) increases proinsulin and insulin content and improves SC-β-cell GSIS.
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