TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss-of-function of TDP-43
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PROVIDER: PRJNA1200700 | ENA |
REPOSITORIES: ENA
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Project description:Cytoplasmic aggregation and nuclear depletion of TDP-43 are hallmarks of several age-related neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been a major challenge. Here, we produced amyloid-like fibrils from the recombinant low-complexity-domain of TDP-43, and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cell lines and iPSC-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin- and p62-accumulation, and recruit nuclear endogenous TDP-43 leading to nuclear-loss-of-function-driven disease-specific cryptic splicing defects. Cytoplasmic TDP-43 aggregates exhibit, with time, distinct heterogeneous morphologies as in patients including compacted, filamentous or fragmented, through the activation of cellular protein clearance pathways. Cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify templated aggregation of TDP-43 as a key mechanism driving both cytoplasmic gain- and nuclear-loss-of-function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.
2025-03-28 | GSE284828 | GEO
Project description:When mutant superoxide dismutase 1 (SOD1) was first linked to amyotrophic lateral sclerosis (ALS), it was thought that ALS is a disease of oxidative stress, but this idea has taken a back seat since the discovery of multiple ALS-linked genes involved in RNA processing and proteostasis. Strikingly, a hallmark of both familial and sporadic ALS is the aggregation of the essential DNA/RNA binding protein TDP-43, which is thought to cause simultaneous loss-of-nuclear function and gain-of-cytoplasmic toxicity. A central unanswered question is what triggers ALS in adult followed by rapid and irreversible progression? Here we report that neuronal cells are particularly prone to oxidative stress to trigger TDP-43 aggregation, which in turn sponges a large subset of microRNAs and proteins, resulting in global mitochondrial imbalance that further elevates the oxidative stress. We propose that this ferocious cycle may underlie ALS onset and progression with oxidative stress as a key disease-driving event.
2020-10-12 | GSE126801 | GEO
Project description:Both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43 contribute to neurodegeneration in ALS and FTD, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43 seeding platform for quantitative, high-throughput assessment of TDP-43 aggregate uptake, cell-to-cell spreading and direct quantification of TDP-43 nuclear function within living cells, while they progress towards pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates are abundantly internalized in human neuron-like cells, efficiently recruit endogenous TDP-43 and form cytoplasmic inclusions reminiscent of ALS/FTD pathology. These neoaggregates progressively drive the nuclear egress of TDP-43 leading to its loss of function. The scope of this project is to identify the signatures involved in the progressive egress of TDP-43 from the nucleus to the cytoplasm.
2025-02-20 | GSE285224 | GEO
Project description:TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.
2023-01-09 | GSE216294 | GEO
Project description:Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in disease.
2024-01-31 | PXD042382 | Pride
Project description:The integrated stress response (ISR) is a major element of translation control. The ISR is beneficial in responding to acute stresses, but in human disease a chronic, persistent stress response can contribute to the disease process. Many studies manipulate the ISR by targeting just one protein. However, viral proteins have evolved to target many elements of this system. We examined the Herpesvirus protein ORF57, and determined the protein interaction network and identified that it binds to many proteins linked to the ISR. We show that expressing ORF57 in neuronal SH-SY5Y cells reduces the ISR, inhibiting the accumulation of G3BP1 positive stress granules. We then applied the ORF57 vector to examine the effects on aggregation of TDP-43, which accumulates in neurodegenerative diseases such as amyotrophic lateral sclerosis. We demonstrate that expressing ORF57 changes the dynamics of TDP-43 aggregation and granule formation, reducing the accumulation of aggregated TDP-43 by 36% and increasing the rate of dispersion of TDP-43 aggregates by 2.45-fold. These data suggest that viral proteins, such as ORF57, can be repurposed and applied to inhibit the types of chronic, persistent stress responses in mammalian cells that are associated with neurodegenerative diseases.
2024-08-09 | PXD039246 | Pride
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.
2024-04-19 | GSE264018 | GEO
Project description:Cytoplasmic aggregates of TDP-43 are found in neuronal and skeletal muscle diseases yet it is not understood how these protein aggregates relate to the biological function of TDP-43. By examining normal skeletal muscle formation, we discovered TDP-43 redistributes from the nucleus into the cytoplasm and forms higher-ordered aggregates. These skeletal muscle TDP-43 aggregates adopt an amyloid-like structure capable of binding RNA. In skeletal muscle, TDP-43 binds UG-rich, sarcomeric mRNAs and oligomerizes on these long mRNA transcripts facilitating amyloid formation. Tissue specific genetic deletion of TDP-43 in skeletal muscle disrupts the formation and maintenance of the sarcomere and mislocalizes sarcomeric mRNAs. Thus, cytoplasmic, amyloid-like TDP-43 aggregates that traffic mRNAs could serve as a precursor to pathological TDP-43 aggregates common in degenerative neuromuscular disease.
2018-09-05 | GSE104796 | GEO
Project description:Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely ”hijacked” by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA-protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.
2019-12-03 | GSE141303 | GEO
Project description:Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.
2023-06-24 | GSE235312 | GEO