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Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress

ABSTRACT: Neurodegeneration-associated mutations affect the dynamics of transient cytoplasmic stress granule (SG). However, it is unclear if and how aberrant SG behavior is linked to the downstream formation of protein aggregates and other molecular defects that persist after stress subsides. Using subcellular fractionation combined with RNA-seq (CeFra-seq) we characterize the global mRNA localization landscape in human pluripotent stem cell-derived motor neuron (PS-MN). Using CeFra-seq and quantitative proteomics, we find that transient stress leads to a widespread reshaping of mRNA and protein localization that recapitulates key molecular phenotypes of Amyotrophic Lateral Sclerosis (ALS). While the substantial reorganization of the global mRNA localization landscape is largely reversible in wild type PS-MNs, we find that cells harboring ALS-linked mutations in HNRNPA2B1 are unable to recover and display a delayed-onset increase in neuronal cell death in response to stress. Our findings reaffirm the importance of stress-induced molecular mechanisms in the formation of molecular disease pathology of ALS and highlight the importance of targeting SG-relevant molecular mechanisms in the development of therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157467 | GEO | 2021/08/01

REPOSITORIES: GEO

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Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress

Project description:Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress

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Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms

Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here, we show that nano-size polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. Additionally, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing TDP-43’s condensation and solidification. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

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G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress

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Spatio-temporal Proteomic Analysis of Stress Granule disassembly using APEX Reveals Regulation by SUMOylation and links to ALS pathogenesis

Project description:Cytoplasmic stress granules (SG) are membraneless organelles that form in response to a variety of cellular stresses by phase-separation of proteins associated with non-translating mRNAs. SG have recently been linked with neurodegeneration, including ALS, however there has been no systematic investigation of SG composition in normal and disease contexts. We created a proximity proteomics platform by using multiple ascorbate peroxidase (APEX2) baits to comprehensively characterize the spatio-temporal organization of SG in normal and disease (ALS-like) conditions. Multi-bait APEX enhanced sensitivity and enabled cross-validation, leading to the mass spectrometric discovery of 109 additional SG proteins, and internal SG substructures at proteomic resolution. A proteomic analysis of SG disassembly over time revealed a group of 349 proteins recruited specifically during SG disassembly, which we named disassembly-engaged proteins (DEPs), including SUMO ligases. A parallel study of SG disassembly in the presence of C9ORF72-associated dipeptides, which are found in patients with ALS and frontotemporal dementia revealed impaired SG disassembly and DEP recruitment, which may be linked to neurodegeneration. Finally, broad SUMOylation of SG proteins was required for SG disassembly, and impaired by C9ORF72-associated dipeptides. Altogether, our study provides a valuable resource, and dissects the SG spatio-temporal proteomic landscape, revealing basic and disease-relevant mechanisms of SG dynamics.

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Stress granules protect ER-exit sites from TDP43 aggregation

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2023-06-30 | PXD017887 | Pride

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Project description:Cells respond to stress by blocking translation, rewiring metabolism, and forming transient mRNP assemblies called stress granules (SGs). After stress release, re-establishing homeostasis requires energy-consuming processes. However, the molecular mechanisms whereby cells restore energy production to disassemble SGs and reinitiate growth after stress remain poorly understood. Here we show that, upon stress, the ATP-producing enzyme Cdc19 forms inactive amyloids, and that their rapid re-solubilization is essential to restore energy production and SG disassembly. Cdc19 re-solubilization is initiated by the glycolytic metabolite fructose-1,6-bisphosphate (FBP), which directly binds Cdc19 amyloids and facilitates conformational changes that allow Hsp104 and Ssa2 chaperone recruitment. FBP then promotes Cdc19 tetramerization and activity, which together with trehalose breakdown boosts glycolysis to further enhance SG disassembly. Together, these results provide a molecular mechanism protecting cells during stress by directly coupling metabolism and ATP production with SG dynamics via regulation of Cdc19 amyloids.

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ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

Project description:Mutations in Matrin 3 have recently been linked to ALS, though the mechanism of disease in these patients is still unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry experiments in NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin in mRNA transport centered around proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and the mRNA of ALS linked proteins TDP-43 and FUS. Our findings demonstrate the first pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

2017-11-15 | PXD007710 | Pride

Uncapped mRNAs during heat stress

Project description:Tudor staphylococcal nuclease (TSN or Tudor-SN; also known as SND1) is an evolutionarily conserved protein involved in transcriptional and post-transcriptional regulation of gene expression in animals. Although TSN was found to be indispensable for normal plant development and stress tolerance, the molecular mechanisms underlying these functions remain elusive. Here we show that Arabidopsis thaliana TSN is essential for integrity and function of cytoplasmic messenger ribonucleoprotein (mRNP) complexes called stress granules (SG) and processing bodies (PB), sites of post-transcriptional gene regulation during stress. TSN associates with SG following their microtubule-dependent assembly and plays a scaffolding role in both SG and PB. The enzymatically active tandem repeat of four SN domains is crucial for targeting TSN to the cytoplasmic mRNA complexes, and is sufficient for the cytoprotective function of TSN during stress. Furthermore, our work connects the cytoprotective function of TSN with its positive role in stress-induced mRNA decapping. While stress led to a pronounced increase in the accumulation of uncapped mRNAs in wild type plants, this increase was abrogated in TSN knockout plants. Taken together, our results establish TSN as a key enzymatic component of catabolic machinery responsible for the processing of mRNAs in the cytoplasmic mRNP complexes during stress.

2014-11-21 | GSE63522 | GEO

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