What biological pathways is TDP-43 known to be part of?

TDP-43 functions in seven major biological pathways: RNA metabolism, nucleocytoplasmic transport, stress response, mitochondrial function, synaptic function, inflammatory responses, and cell cycle regulation.

Abstract

Forty studies report that TDP-43 participates in a network of biological pathways. In several papers, TDP-43 regulates RNA metabolism by controlling alternative splicing, cryptic exon inclusion, and mRNA stability. Other studies document that TDP-43 affects nucleocytoplasmic transport by disrupting nuclear pore complex integrity and altering protein–RNA distribution. Reports also describe its role in stress response and protein quality control through modulation of stress granule dynamics, phase separation, and aggresome formation. In addition, TDP-43 has been linked to mitochondrial function via binding mitochondrial mRNAs and disrupting respiratory complex assembly, as well as to synaptic function and neurotransmitter regulation through effects on receptor recycling and synaptic protein expression. Some papers further implicate the protein in inflammatory and immune responses via activation of NF‑κB and inflammasome pathways, and in cell cycle regulation and DNA repair by modulating targets such as cyclin-dependent kinase expression and double-strand break repair.

Seven primary pathways emerge from these studies:

1. RNA metabolism and processing
2. Nucleocytoplasmic transport
3. Stress response and protein quality control
4. Mitochondrial function
5. Synaptic function and neurotransmitter regulation
6. Inflammatory and immune responses
7. Cell cycle regulation and DNA repair

Diverse experimental systems—including mouse models, cultured cells, and iPSC-derived neurons—support TDP-43’s multifaceted functions across these interrelated pathways.

Methods

We analyzed 40 sources from an initial pool of 493, using 6 screening criteria. Each paper was reviewed for 3 key aspects that mattered most to the research question. More on methods

Paper search

Using your research question “What biological pathways is TDP-43 known to be part of?”, we searched across over 126 million academic papers from the Semantic Scholar corpus. We retrieved the 493 papers most relevant to the query.

Screening

We screened in sources based on their abstracts that met these criteria:

• Molecular Pathway Analysis: Does the study investigate TDP-43’s molecular interactions and/or its role in specific cellular processes?
• TDP-43 Function: Does the study examine pathway-related functions of wild-type and/or mutant TDP-43?
• Experimental Design: Does the study include experimental data from in vitro and/or in vivo investigations with mechanistic insights?
• Study Type: Is the study either primary research with mechanistic investigation OR a systematic review/meta-analysis of TDP-43 pathways?
• Mechanistic Detail: Does the study provide specific molecular pathway or mechanistic investigation beyond mere observational findings?
• Evidence Quality: Is the study based on systematic analysis rather than being an opinion piece or narrative review?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• Specific Biological Pathways Involving TDP-43:

  • Extract all explicitly mentioned biological pathways or cellular processes that TDP-43 is involved in. Look in the methods, results, and discussion sections. Specific areas to focus on:
  • RNA metabolism processes
  • Splicing regulation
  • Mitochondrial interactions
  • Neuronal function pathways
  • If multiple pathways are mentioned, list them all. If a pathway is described but not explicitly named, summarize the description.
  • If no clear pathways are identified, write “No specific pathways explicitly described.”

• Molecular Interactions and Binding Partners of TDP-43:

  • Identify and list all molecular interactions and binding partners mentioned in the study.
  • Search in:
    • Results sections describing protein interactions
    • Methods describing protein complex analyses
    • Discussion sections discussing molecular relationships
  • Extract:
    • Protein binding partners
    • RNA binding targets
    • Specific binding sites or motifs
    • Co-purifying proteins or complexes
  • If multiple interactions are found, list all. If no interactions are described, write “No molecular interactions reported.”

• Functional Consequences of TDP-43 Interactions:

  • Extract specific functional outcomes or consequences resulting from TDP-43 interactions or modifications.
  • Look for:
    • Changes in cellular processes
    • Impact on gene expression
    • Neurological or cellular effects
    • Pathological consequences of interactions
  • Prioritize direct functional descriptions, not just descriptive observations.
  • If multiple consequences are found, list all. If no clear functional outcomes are described, write “No specific functional consequences reported.”

Results

Characteristics of Included Studies

Study Design

• In vitro study
• In vivo mouse model and in vitro studies
• Review

Pathways Investigated

• RNA metabolism
• Immune response
• Phagocytosis
• Nucleocytoplasmic transport
• Stress granule formation

Thematic Analysis

RNA Processing and Regulation Pathways

Study

• RNA Processing Function
• Specific Targets/Mechanisms
• Cellular Impact

Findings

• TDP-43 regulation of specific RNA processes

Stress Response and Protein Quality Control Pathways

Study

• Stress Response Mechanism
• Protein Quality Control Function
• Cellular Impact

Findings

• TDP-43 effects on stress granules, gene expression, and cellular homeostasis

Synaptic Function and Neurotransmitter Pathways

Study

• Synaptic Function
• Neurotransmitter Regulation
• Cellular Impact

Findings

• Regulation of receptor recycling and neurotransmitter release

Pathway Interactions and Integration

Primary Pathway Interactions

• RNA Processing
• Stress Response and Protein Quality Control
• Interconnections in cellular functions involving TDP-43

References

• Liam Chen (2020). The important functional role of TDP-43 plays in amyotrophic lateral sclerosis-frontotemporal dementia. Neural Regeneration Research
• L. Heyburn, C. Moussa (2016). TDP-43 overexpression impairs presynaptic integrity. Neural Regeneration Research
• Additional references omitted for brevity.