Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CHIP protects lysosomes from CLN4 mutant-induced membrane damage

ABSTRACT: Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome-related diseases. Here we generated and characterized iPSC-derived neurons (i3Neuron) bearing Ceroid Lipofuscinosis Neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosome damages, caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302082 | GEO | 2025/07/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A ubiquitin ligase protects lysosomes from CLN4 mutant-induced membrane damages

Project description:Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome related diseases. Here we use organelle-specific proteomics in iPSC derived neurons (i3Neuron) and an in vitro lysosome damaging assay to demonstrate that lysosome damage, caused by the aggregation of Ceroid Lipofuscinosis Neuronal 4 (CLN4) linked DNAJC5 mutants on lysosomal membranes, serves as a critical pathogenic linchpin in CLN4 associated neurodegeneration. Intriguingly, in non neuronal cells, a ubiquitin dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4 associated lysotoxicity. Genome wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin dependent lysosome protection. Importantly, CHIP lysosome protection function is transferrable, as ectopic CHIP improves lysosomal function in CLN4 i3Neurons, and effectively alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 disease model. Our study establishes CHIP mediated microautophagy as a key organelle damage guardian that preserves lysosome integrity, offering new insights into therapeutic development for CLN4 and other lysosome related neurodegenerative diseases.

2024-12-11 | MSV000096646 | MassIVE

CLN6 deficiency causes selective changes in the lysosomal protein composition

Project description:Neuronal Ceroid Lipofuscinosis 6 (NCL6) is a neurodegenerative, lysosomal storage disease. It is caused by a deficiency of the transmembrane protein ceroid-lipofuscinosis neuronal protein 6 (CLN6) that resides in the endoplasmic reticulum. In this project the lysosomal proteome changes in NCL6 were investigated. Therefore, lysosomes were purifiedfrom liver tissue of CLN6 knock-out mice, the proteins were labeled by TMT and the CLN6 proteome was compared to wild type controls. Lysosome purification was obtained by either isolation of tritosomes or differential centrifugation generating 20,000 g pellets.

2024-10-28 | PXD016599 | Pride

Gene expression in leucocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

Project description:Identification of differentially expressed genes in lecocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

2011-10-01 | GSE30369 | GEO

Assessment of Neurological Deterioration in Subjects with LINCL

Project description:<p>Late infantile ceroid lipofuscinosis (LINCL) is a rare, rapidly progressing lysosomal storage disease resulting from mutations in the CLN2 gene that lead to deficiency in the lysosomal protease tripeptidyl peptidase I (TPP-I). The symptoms are largely neurological with onset at 2-4 years age with progression to death at age 8-12 yrs. The rareness of the disease and the likelihood of non-uniform progression depending on genotype together limit the data available regarding the natural history of disease progression. Current neurological rating scales are used to give an overall quantitative description of the disease but the categories are generally broad and imprecise.</p> <p>With that background, the primary focus of this study is to use clinical rating scales and magnetic resonance imaging methods to define the natural history of LINCL and to provide objective and sensitive surrogates for neurological status and the impact of experimental treatments in children with LINCL. Together these parameters will be applicable to future clinical studies of novel therapies for LINCL and should be transferrable to other neurological lysosomal storage diseases. Subjects will be assessed at 2 visits separated by ≥1 yr. Brain morphometry, water self-diffusion coefficients and spectroscopic data will be obtained via magnetic resonance. Resulting MRI biomarkers will be compared with neurological assessment of disease severity using the Weill-Cornell LINCL rating scale.</p>

| phs001575 | dbGaP

The Batten disease gene product CLN3 is required for the efflux of glycerophosphodiesters from lysosomes

Project description:The lysosome has many cellular roles, including degrading and recycling macromolecules and signaling to the mTORC1 growth regulator. Lysosomal dysfunction occurs in various human diseases, including common neurodegenerative diseases as well as monogenic lysosomal storage disorders (LSDs). For most LSDs the causal genes have been identified, but in many cases the function of the implicated gene is unknown. Here, we develop the LysoTag mouse line for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We apply it to the study of CLN3, a lysosomal transmembrane protein of unclear function whose loss causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and stable isotope tracing experiments show that CLN3 is required for their lysosomal egress. Loss of CLN3 also alters upstream glycerophospholipid catabolism in the lysosome. Our results suggest that CLN3 is a lysosomal effluxer of GPDs and reveal Batten disease as the first, to our knowledge, neurodegenerative LSD with a primary defect in glycerophospholipid metabolism.

2022-07-11 | PXD018624 | Pride

Synapse alterations precede neuronal damage and storage pathology in a human cerebral organoid model of CLN3-Juvenile Neuronal Ceroid Lipofuscinosis

Project description:We developed an invitro model for Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) using isogenic CLN3 mutated human iPS cell lines and performed transcriptomic profiling of brain organoids derived from these lines to identify transcriptomic changes in the early developing brain model.

2020-01-03 | GSE137420 | GEO

Gene expression in leucocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease)

Project description:Identification of differentially expressed genes in lecocytes of patients with autosomal dominat neronal ceroid lipofuscinosis (Kufs disease) Leucocyte RNA expression of consanguineous Kufs disease cases (n=4) and unrelated healthy controls (n=4)

2011-09-30 | E-GEOD-30369 | biostudies-arrayexpress

The expression of genes encoding palmitoylated proteins in axonal and synaptic compartments is affected in CLN1/PPT1 transfected neuronal cells

Project description:CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 is also related to specific functions in the synaptic compartment. The aim of this study was to recognize molecular signatures and functional modules connected with CLN1. We utilized differentiated SH-SY5Y neuroblastoma cells to overexpress wild type CLN1 (SH-p.wtCLN1) and introduced selected mutations previously detected in CLN1 patients. wtCLN1 and two mutant CLN1- harbouring cell lines were characterized by whole transcriptomic profiling using RNA-seq, to subsequently identify differentially expressed genes (DEGs) and alterations in related neuronal functions.

2017-09-20 | GSE98834 | GEO

Transcriptional control of lysosomal homeostasis by the disease-related CLN3 membrane protein

Project description:CLN3 is a type II transmembrane protein localized in the late endosomal/lysosomal compartment. A deficiency of CLN3 leads to the development of a certain type of Neuronal Ceroid Lipofuscinosis, a neurodegenerative disorder of childhood caused by aggregation of undegraded material in the lysosomal compartment. Cultured, immortalized wild type and Cln3(Δex7/8) cerebellar granule cells were used in this project to determine the influence of Cln3 deficiency on the proteome of the lysosomal compartment. For this purpose, cells were labelled by stable amino acid labelling in cell culture and lysosomes were isolated by magnetic beads.

2019-05-13 | PXD004548 | Pride

Dataset for analyzing lysosomal proteome using MiSE method

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.

2024-09-25 | PXD056201 | JPOST Repository

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data