Heterogeneity in Lysosomal Storage Disorders
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ABSTRACT:
PROVIDER: PRJNA1033710 | ENA |
REPOSITORIES: ENA
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Project description:Heterogeneity in Lysosomal Storage Disorders
| PRJNA1033709 | ENA
Project description:smMIP based NGS assay for diagnosis of Lysosomal Storage Disorders in India
| PRJEB50490 | ENA
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.
2024-06-11 | GSE263252 | GEO
Project description:Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of GM2 ganglioside and GA2 glycolipid. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases
2025-02-10 | GSE275408 | GEO
Project description:Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with many human diseases, such as lysosomal storage disorders (LSD). How the cell detects lysosomal defects and then restores lysosomal function remain incompletely understood. Here, we show that STING mediates a common neuroinflammatory gene signature in three distinct lysosomal storage disorders, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi brain tissue revealed that STING also mediates the expression of a broad panel of lysosomal genes that are part of the CLEAR (Coordinated Lysosomal Expression and Regulation) signaling pathway, which is regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-seq analysis show that STING regulates lysosomal gene expression in microglia in LSD mice. Mechanistically, we show that STING activation in both human and mouse cells leads to TFEB dephosphorylation, nuclear translocation, and expression of target lysosomal genes. In addition, STING-mediated TFEB activation requires its proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Functionally, we show that the STING-proton channel-TFEB axis plays a role in facilitating lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control and recovery mechanism that responds to both genetic and chemically induced lysosomal dysfunction.
2025-04-23 | GSE283768 | GEO
Project description:Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Clinical findings in affected males revealed a milder clinical course with ~15% residual AGAL activity and borderline plasma lyso-Gb3Cer levels. Kidney biopsies did not show lysosomal storage. Laboratory investigations documented intracellular retention of mutated AGAL with resulting endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which were alleviated with BRD4780, a small molecule clearing misfolded proteins from the early secretory compartment. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense AGAL variants. We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms.
2025-03-01 | GSE271756 | GEO
Project description:A zebrafish forward genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in the lysosomal hydrolase Cathepsin L that manifests the hallmarks of human lysosomal storage diseases. In uninfected mutants, macrophages progressively accumulate undigested material in their lysosomes, leading to impaired migration and the accumulation of unengulfed cell debris. During mycobacterial infection, these vacuolated macrophages cannot migrate to phagocytose infected macrophages undergoing apoptosis in the tuberculous granuloma. Consequently, unengulfed apoptotic macrophages undergo secondary necrosis causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal accumulations similarly impair migration to newly infecting mycobacteria. We find that important aspects of this phenotype are recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of alveolar macrophages from smokers exhibit lysosomal accumulations and do not migrate to Mycobacterium tuberculosis. This incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.
2015-10-21 | GSE74196 | GEO
Project description:Reactivation of mTOR signaling slows neurodegeneration in a lysosomal storage disease
| PRJNA1150620 | ENA
Project description:Lysosomes are critical for cellular metabolism and heterogeneously involved in various cellular processes such as endocytosis, autophagy and senescence. The ability to measure lysosomal metabolic heterogeneity is essential for understanding its physiological roles. We therefore built a single-lysosome mass spectrometry (SLMS) platform integrating lysosomal patch-clamp recording and induced nanoESI/MS that enabled concurrent metabolic and electrophysiological profiling of individual enlarged lysosomes.
2021-04-14 | MSV000087208 | GNPS
Project description:Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins enriched at lysosomes mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked with longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using large-scale proteomic profiling, we systemically profiled lysosome-enriched proteomes in association with different longevity mechanisms. We further discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we discovered lysosomal heterogeneity across tissues as well as the specific enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity at different levels and provides resources for understanding the contribution of lysosomal proteome dynamics in modulating signal transduction, organelle crosstalk and organism longevity.
2022-12-15 | MSV000090909 | MassIVE