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Key Event: 2451

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, TDP-43 aggregation

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
TDP-43 aggregation
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Increase in ROS leading to human ALS KeyEvent Shihori Tanabe (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Transactivation response DNA-binding protein 43 (TDP-43) is an essential, highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) primarily localized to the cell nucleus, where it participates in RNA processing, alternative splicing, transcriptional regulation, and mRNA stability.

In pathological states—particularly in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP)—TDP-43 undergoes nuclear-to-cytoplasmic mislocalization, hyperphosphorylation, ubiquitination, and C-terminal fragmentation. Excessive cellular stressors, including elevated reactive oxygen species (ROS), facilitate abnormal liquid-liquid phase separation (LLPS) transitions, driving TDP-43 into irreversible liquid-to-solid transitions and the formation of insoluble cytoplasmic aggregates (inclusion bodies). This process impairs normal cellular proteostasis, disrupts RNA metabolism through loss of physiological nuclear function, and mediates cytotoxic gain-of-function cascades in neuronal cells.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

  • Biochemical & Solubility Fractionation:

    • Sequential Protein Extraction: Separation of cell/tissue lysates into detergent-soluble (e.g., RIPA, Triton X-100) and detergent-insoluble (e.g., Urea/SDS, formic acid) fractions, followed by immunoblotting to quantify insoluble TDP-43 species.

    • Post-Translational Modification Probing: Western blotting using phospho-specific antibodies targeting pathological epitopes (e.g., Ser409/Ser410) and full-length vs. truncated C-terminal fragments (~25 kDa and ~35 kDa).

  • Immunocytochemistry & Immunohistochemistry (ICC/IHC):

    • Subcellular Localization & Quantification: Confocal microscopy detecting cytoplasmic puncta/inclusions vs. nuclear depletion in primary motor neurons, iPSC-derived motor neurons, or spinal cord tissue slices.

    • Colocalization Analysis: Co-staining with stress granule markers (e.g., G3BP1, TIA-1) and ubiquitin/p62 to verify inclusion maturation.

  • Fluorescence Recovery After Photobleaching (FRAP):

    • In live-cell imaging setups expressing GFP/mCherry-tagged TDP-43 to assess loss of mobility and liquid-to-solid phase transition kinetics under stressor conditions.

  • High-Throughput / Quantitative Assays:

    • ELISA / Meso Scale Discovery (MSD): Quantitative sandwich immunoassays for phosphorylated TDP-43 (p-TDP-43) in cellular lysates or biofluids (CSF/plasma).

    • Filter Retardation Assays: Cell lysate filtration through nitrocellulose membranes (e.g., 0.2 micro m) to isolate and quantify high-molecular-weight aggregates.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Taxonomic Applicability: Primates (Human), Rodents (Mouse, Rat)

Domain Taxon Name Scientific Name Evidence
Eukaryota Human Homo sapiens Strong (post-mortem tissue, patient iPSC lines)
Eukaryota Mouse Mus musculus Strong (transgenic/knock-in models)
Eukaryota Rat Rattus norvegicus Moderate (in vitro primary cultures, rodent models)

References

List of the literature that was cited for this KE description. More help

Cohen, T. J., Hwang, A. W., Unger, T., Trojanowski, J. Q., & Lee, V. M. Y. (2011). Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking. The EMBO Journal, 31(5), 1241–1252. https://doi.org/10.1038/emboj.2011.471 Cited by: 290

Dewey, C. M., Cenik, B., Sephton, C. F., Dries, D. R., Mayer, P., Good, S. K., Johnson, B. A., Herz, J., & Yu, G. (2011). TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Molecular and Cellular Biology, 31(6), 1098–1108. https://doi.org/10.1128/mcb.01279-10 Cited by: 495

Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., Beach, T. G., Buratti, E., Baralle, F., Morita, M., Nakano, I., Oda, T., Tsuchiya, K., & Akiyama, H. (2008). Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Annals of Neurology, 64(1), 60–70. https://doi.org/10.1002/ana.21425 Cited by: 979

Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., & Lee, V. M.-Y. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314(5796), 130–133. https://doi.org/10.1126/science.1134108 Cited by: 8344

Rabdano, S. O., Izmailov, S. A., Luzik, D. A., Groves, A., Podkorytov, I. S., & Skrynnikov, N. R. (2017). Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-10574-w Cited by: 67

Walker, A. K., Soo, K. Y., Sundaramoorthy, V., Parakh, S., Ma, Y., Farg, M. A., Wallace, R. H., Crouch, P. J., Turner, B. J., Horne, M. K., & Atkin, J. D. (2013). ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. PLoS ONE, 8(11), e81170. https://doi.org/10.1371/journal.pone.0081170 Cited by: 234