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The small molecule lipoamide modulates stress granule condensation with beneficial outcomes for familial amyotrophic lateral sclerosis models

ABSTRACT: We have evaluate the in-situ targets of lipoamide - a compund that causes alteration of the fluidity of in-vito FUS condensate and dissolves stress granules in cells - in Hela cells stressed with 1 mM arsenate. We have used quantitative proteomics based thermal proteome profiling to characterise the system-wide targets of this compound. Conventional TPP protocol described in Becher et al., 2016 was used.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sindhuja Sridharan

LAB HEAD: Mikhail M. Savitski

PROVIDER: PXD039501 | Pride | 2025-05-09

REPOSITORIES: Pride

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			Action	DRS
	F100519.dat	Other
	F100523.dat	Other
	F100528.dat	Other
	F100533.dat	Other
	F100537.dat	Other

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Similar Datasets

The small molecule lipoamide modulates stress granule condensation with beneficial outcomes for familial amyotrophic lateral sclerosis models

Project description:Neurodegenerative diseases like amyotrophic lateral sclerosis are often associated with mutations in proteins which can form stress granules by liquid-liquid phase separation (LLPS). Formation of these condensate phases requires a complex molecular grammar for protein-protein interactions which, when aberrant, can lead to altered condensation and disease phenotypes. We asked whether condensation of ALS-associated proteins could be a drug target. Screening identified lipoamide, a small molecule which specifically reduces cytoplasmic condensation (stress granules) of FUS and other ALS-associated proteins. In vitro, lipoamide partitions into and alters the physical properties of condensates made by FUS, similarly in cells lipoamide partitions into stress granules. Thermal proteome profiling showed lipoamide stabilises proteins with R/Y-rich intrinsically disordered domains in cells, including SRSF1 and SFPQ, two stress granule proteins which are necessary for lipoamide activity. In animals, lipoamide reduces aging-associated aggregation of a stress granule protein and improves neuronal morphology and recovers motor defects caused by ALS-associated FUS and TDP43 mutations. Lipoamide is a well-tolerated specific small molecule modulator of stress granule condensation with drug-like potential.

2025-05-09 | PXD039670 | Pride

Diversity of early astrocyte reactive profiles in familial amyotrophic lateral sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the uniformity of their reactive transformation in different genetic forms of ALS remains unresolved. Here we begin to systematically examine this issue by performing RNA sequencing on highly enriched and serum-free human induced pluripotent stem cell derived astrocytes from patients with VCP, SOD1 and FUS mutations. The RNA-seq samples in this collection have been used to reveal that diverse fALS mutations lead to molecularly distinct reactive transformation in their basal state.

2021-09-20 | E-MTAB-10916 | biostudies-arrayexpress

Amyotrophic Lateral Sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity

Project description:We employ CLIP-Seq, RNA-Seq and Ribo-Seq in cultured neurons expressing R495X or wild-type FUS to identify effects of the mutation on the FUS targetome and on the neuronal transcriptome at the expression and translation level

2017-11-01 | GSE106386 | GEO

Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in Amyotrophic Lateral Sclerosis

Project description:Determination of RNAs bound by wildtype and P525L mutant FUS in human iPSC-derived motoneurons using PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation)

2019-06-13 | GSE118347 | GEO

Multiomics approach reveal novel insights in FUS driven Juvenile Amyotrophic Lateral Sclerosis: a family quartet analysis

Project description:We have identified a novel de novo variation in FUS gene in a sporadic juvenile ALS patient. FUS is an RNA-binding protein actively involved in various aspect of nucleic acid metabolism. We performed RNA-seq to identify altered transcriptome in juvenile ALS.

2024-05-25 | GSE232929 | GEO

Genome wide analysis points towards subtype specific diseases in different genetic forms of Amyotrophic Lateral Sclerosis

Project description:We established iPSCs from healthy donors, FUS-ALS and SOD1-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to FUS- and SOD mutations in ALS disease, we have performed a comprehensive gene expression profiling study using microarray hybridization of the iPSC-derived MN models from control individuals and carefully compared with those from FUS-ALS and SOD1-ALS patients. In addition, we further analyzed previously published independent datasets containing the genome-wide RNA profiling of iPSC-derived MN samples from patients with FUS and SOD1 mutations and controls. This microaray dataset GSE10638 (Fujimori et al., 2018) was retrieved from GEO database and was screened to identifiy potential drug candidates which suppressed the detected ALS-related phenotypes of these ALS models. Finally, we made a systematic comparison with our results to the ones independently obtained previously.Here through this study, we create a gene profile of ALS by analyzing the differentially expressed genes (DEGs), the kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome as well as transcription factor profiles (TF) that would identify altered functional/molecular signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs) which stands validation across the different datasets (including different differentiation protocols etc.). By doing so we provide condensed pathophysiological pathways of FUS-ALS and SOD1-ALSto better understand the biological mechanisms underlying motor neuron disease.

2020-09-21 | GSE158264 | GEO

Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis.

Project description:Recent advances in the genetics of amyotrophic lateral sclerosis (ALS) have provided key mechanistic insights to the pathogenesis of this devastating neurodegenerative disease. Among many etiologies for ALS, the identification of mutations and proteinopathies in two RNA binding proteins, TDP-43 (TARDBP or TAR DNA binding protein 43) and its closely related RNA/DNA binding protein FUS (fused in sarcoma), raises the intriguing possibility that perturbations to the RNA homeostasis and metabolism in neurons may contribute to the pathogenesis of these diseases. Although the similarities between TDP-43 and FUS suggest that mutations and proteinopathy involving these two proteins may converge on the same mechanisms leading to neurodegeneration, there is increasing evidence that FUS mutations target distinct mechanisms to cause early disease onset and aggressive progression of disease. This review focuses on the recent advances on the molecular, cellular and genetic approaches to uncover the mechanisms of wild type and mutant FUS proteins during development and in neurodegeneration. These findings provide important insights to understand how FUS mutations may perturb the maintenance of dendrites through fundamental processes in RNA splicing, RNA transport and DNA damage response/repair. These results contribute to the understanding of phenotypic manifestations in neurodegeneration related to FUS mutations, and to identify important directions for future investigations. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.

| S-EPMC5003642 | biostudies-literature

Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis.

Project description:The Pre-familial Amyotrophic Lateral Sclerosis (Pre-fALS) study is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis. Our goals were to (1) explore participants' decisions of whether to learn results of presymptomatic testing or not; (2) understand the psychosocial impact of these decisions; and (3) assess preferences for receiving results by telephone or in person.The sample for this substudy comprised 20 participants drawn randomly from autosomal dominant mutant superoxide dismutase 1 families in the Pre-fALS study. Twenty participants completed a semistructured phone interview; prominent themes were identified and rated.Fourteen participants chose to learn results; six had mutant superoxide dismutase 1 and eight had wild-type superoxide dismutase 1. Of the six who initially elected nondisclosure, three were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short term.We recommend that (1) those considering presymptomatic genetic testing should undergo professional counseling to help decide whether to learn results; (2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; and (3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves.

| S-EPMC4039017 | biostudies-other

MiR-129-5p downregulates HuD expression impairing neuritogenesis in Amyotrophic Lateral Sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) involves the degeneration of brain and spinal cord motor neurons. Mutations in Superoxide Dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and Fused-in-Sarcoma (FUS) account for 20-30 % of the familial ALS (fALS) cases. The RNA-binding proteins TDP-43 and FUS function in mRNA and miRNA biogenesis. MiRNAs are required for survival of neurons and deregulation of miRNA expression has been reported in several neurodegenerative disorders. Here, we report the dysregulation of DROSHA, DGCR8, and DICER in human neuroblastoma SH-SY5Y cells expressing the ALS-associated SOD1(G93A) mutant protein. MiRNA profiling in SH-SY5Y/SOD1(G93A) cells and transgenic SOD1(G93A) mice revealed upregulation of miR-129-5p at the early stage of disease. Moreover, miR-129-5p is also upregulated in lymphocytes of sporadic ALS patients. We demonstrate that miR-129-5p targets ELAVL4/HuD mRNA by binding to its 3’ UTR, which reduces HuD expression and impairs differentiation and neurite outgrowth. Conversely, treatment with an antagomir or complementation with HuD protein restores neuritogenesis. Collectively, our study identifies miR-129-5p and HuD as key regulators of neuronal differentiation and as potential therapeutic targets for ALS.

2018-02-01 | GSE94379 | GEO

Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.

Project description:Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease, motor neuron disease). Insoluble forms of mutant SOD1 accumulate in neural tissues of human ALS patients and in spinal cords of transgenic mice expressing these polypeptides, suggesting that SOD1-linked ALS is a protein misfolding disorder. Understanding the molecular basis for how the pathogenic mutations give rise to SOD1 folding intermediates, which may themselves be toxic, is therefore of keen interest. A critical step on the SOD1 folding pathway occurs when the copper chaperone for SOD1 (CCS) modifies the nascent SOD1 polypeptide by inserting the catalytic copper cofactor and oxidizing its intrasubunit disulfide bond. Recent studies reveal that pathogenic SOD1 proteins coming from cultured cells and from the spinal cords of transgenic mice tend to be metal-deficient and/or lacking the disulfide bond, raising the possibility that the disease-causing mutations may enhance levels of SOD1-folding intermediates by preventing or hindering CCS-mediated SOD1 maturation. This mini-review explores this hypothesis by highlighting the structural and biophysical properties of the pathogenic SOD1 mutants in the context of what is currently known about CCS structure and action. Other hypotheses as to the nature of toxicity inherent in pathogenic SOD1 proteins are not covered.

| S-EPMC2850267 | biostudies-literature

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