Elicit: TDP-43 Biological Pathways (Public)

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

Papers identified with Elicit search

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:

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.

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:

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.”

Format examples:

Identify and list all molecular interactions and binding partners mentioned in the study.

Extract:

If multiple interactions are found, list all. If no interactions are described, write “No molecular interactions reported.”

Format examples:

Extract specific functional outcomes or consequences resulting from TDP-43 interactions or modifications.

Look for:

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.”

Format examples:

Results

Characteristics of Included Studies

Study Study Design Cellular/Model System Pathways Investigated Key Findings
“TDP‐43 Loss of Function,” 2016 In vitro study Neuronal cell culture Endosomal trafficking The study reported that TDP-43 regulates endosomal trafficking and receptor recycling
Afroz et al., 2023 In vivo mouse model and in vitro studies Mouse models, Amyotrophic Lateral Sclerosis (ALS) patient-derived microglia Immune response, phagocytosis The study reported that targeting TDP-43 C-terminal domain reduces pathology and enhances microglial function
Ayala et al., 2008 In vitro study Human cells Cell cycle regulation The study reported that TDP-43 regulates Cyclin-dependent kinase 6 (Cdk6) expression and cell cycle progression
Chen, 2020 Review Various RNA metabolism, autophagy The review reported that TDP-43 regulates cryptic exon splicing and autophagy pathways
Chou et al., 2017 In vitro and in vivo studies Mouse primary neurons, human fibroblasts, iPSC-derived neurons Nucleocytoplasmic transport The study reported that TDP-43 aggregates disrupt nuclear pore complexes and nucleocytoplasmic transport
Chou et al., 2018 In vitro and in vivo studies Mouse primary neurons, human fibroblasts, iPSC-derived neurons Nucleocytoplasmic transport The study reported that TDP-43 pathology impairs nuclear protein import and RNA export
Deshaies et al., 2018 In vitro and in vivo studies Human cells, mouse models RNA splicing The study reported that TDP-43 regulates alternative splicing of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1)
Fazal et al., 2021 iPSC-derived motor neuron study Human iPSC-derived motor neurons RNA metabolism, axonal transport The study reported that TDP-43 mutations affect RNA processing and axonal transport
Feneberg et al., 2020 In vitro and in vivo studies Mouse primary motor neurons Protein-protein interactions, stress response The study reported that TDP-43 interacts with proteins involved in stress granule formation and endosomal-extracellular transport
Feneberga et al., “Oxidative Stress in Motor Neurons” In vitro and in vivo studies Mouse primary motor neurons Protein-protein interactions, stress response The study reported that TDP-43 mutations affect stress granule formation and extracellular vesicle secretion

Our analysis of the 40 studies on TDP-43 pathways reveals:

The diversity of cellular models and pathways investigated highlights the multifaceted nature of TDP-43’s functions and its potential involvement in various aspects of neurodegeneration.

Based on our analysis, we identified seven primary pathways implicated in the cellular mechanisms of TDP-43:

  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

These diverse pathways highlight the multifaceted role of TDP-43 in cellular function and its potential impact on various aspects of neurodegeneration.

Thematic Analysis

RNA Processing and Regulation Pathways

Study RNA Processing Function Specific Targets/Mechanisms Cellular Impact
Chen, 2020 Cryptic exon splicing regulation Repression of cryptic exons Maintenance of normal transcriptome
Deshaies et al., 2018 Alternative splicing regulation hnRNP A1 pre-mRNA Production of aggregation-prone hnRNP A1B isoform
Fazal et al., 2021 RNA processing, splicing regulation Various mRNA targets Altered gene expression in motor neurons
Gu et al., 2019 mRNA processing Tau mRNA Regulation of tau mRNA stability and exon 10 inclusion
Igaz et al., 2009 RNA splicing No mention found The study reported abnormal RNA splicing caused by TDP-43 C-terminal fragments
Kim et al., 2010 mRNA regulation HDAC6 mRNA Reduced expression of HDAC6
Koehler et al., 2022 Autoregulation, RNA binding TDP-43 mRNA Maintenance of TDP-43 protein levels
Lauranzano et al., 2015 RNA metabolism TARDBP RNA targets Regulation of TDP-43 target gene expression
Ling et al., 2010 RNA processing No mention found The study reported enhanced interaction with FUS/TLS affecting RNA processing
Long et al., 2024 miRNA biogenesis miRNAs Disruption of miRNA processing through Dicer interaction

Our analysis of the included studies suggests that TDP-43 is involved in various RNA processing functions:

These findings suggest that TDP-43 plays a multifaceted role in RNA processing, potentially affecting various cellular processes through its interactions with different RNA targets.

Stress Response and Protein Quality Control Pathways

Study Stress Response Mechanism Protein Quality Control Function Cellular Impact
Chen, 2020 Autophagy regulation Regulation of ATG7 and other autophagy-related genes Maintenance of cellular protein homeostasis
Chou et al., 2017 Stress granule dynamics Interaction with nuclear pore complexes Altered nucleocytoplasmic transport under stress
Feneberg et al., 2020 Stress granule formation Interaction with stress granule proteins Altered stress response under oxidative conditions
Feneberga et al., “Oxidative Stress in Motor Neurons” Stress granule formation Extracellular vesicle secretion Impaired stress response and intercellular communication
Herzog et al., 2019 CREB signaling regulation No mention found Altered gene expression under stress conditions
Koehler et al., 2022 Phase separation Autoregulation of TDP-43 levels Maintenance of TDP-43 protein homeostasis
Luan et al., 2023 Integrated stress response activation Regulation of stress-related gene expression Enhanced TDP-43 aggregation and stress granule formation
Mann et al., 2019 Phase transitions RNA binding-mediated regulation Prevention of neurotoxic TDP-43 aggregation
McGurk et al., 2018 Stress granule localization Interaction with poly(ADP-ribose) Promotion of TDP-43 phase separation
Sidibé et al., 2020 Stress granule dynamics G3BP1 mRNA stabilization Regulation of stress granule assembly

Our analysis of the table reveals several key findings regarding TDP-43’s role in cellular stress responses:

These findings highlight the complex and multifaceted role of TDP-43 in cellular stress responses, with a particular emphasis on stress granule dynamics and phase separation processes.

Synaptic Function and Neurotransmitter Pathways

Study Synaptic Function Neurotransmitter Regulation Cellular Impact
“TDP‐43 Loss of Function,” 2016 Regulation of receptor recycling Affects ErbB4 surface delivery Impaired trophic signaling
Heyburn and Moussa, 2016 Regulation of synaptic protein expression Affects vesicular glutamate levels Altered neurotransmitter release
Sephton et al., 2010 Binding to RNAs involved in synaptic function No mention found Regulation of synaptic gene expression
Herzog et al., 2019 Regulation of dendritic complexity No mention found Altered neuronal morphology and potential synaptic changes
Fazal et al., 2021 Affects axonal transport No mention found Potential impact on synaptic function and neurotransmitter release

Our analysis of the table reveals diverse effects of TDP-43 on synaptic function, neurotransmitter regulation, and cellular impact across the five studies:

The diversity of findings suggests that TDP-43 may have wide-ranging effects on neuronal function, affecting various aspects of synaptic activity, neurotransmitter regulation, and cellular processes. However, the lack of consistent findings across studies indicates a need for further research to establish more definitive patterns of TDP-43’s impact on neuronal function.

Pathway Interactions and Integration

Primary Pathway Connected Pathways Regulatory Points Cellular Outcomes
RNA Processing Stress Response, Synaptic Function Splicing regulation, mRNA stability Altered gene expression, protein homeostasis
Nucleocytoplasmic Transport RNA Processing, Stress Response Nuclear pore complex interactions Disrupted RNA/protein localization, stress granule formation
Stress Response RNA Processing, Protein Quality Control Phase separation, stress granule dynamics Altered stress granule assembly, protein aggregation
Mitochondrial Function Stress Response, DNA Repair Mitochondrial mRNA binding, unfolded protein response Respiratory complex disruption, oxidative stress
Synaptic Function RNA Processing, Protein Quality Control Receptor recycling, synaptic protein expression Altered neurotransmission, synaptic plasticity
Inflammatory Response Stress Response, Mitochondrial Function NF-κB and NLRP3 inflammasome activation Microglial activation, neuroinflammation
DNA Repair RNA Processing, Stress Response Double-Strand Break (DSB) repair, R-loop metabolism Genome stability, cellular survival

Our analysis of the pathway interactions and integration reveals:

The studies we analyzed suggest interconnections between multiple pathways involving TDP-43, potentially indicating its multifaceted cellular functions. These interconnections may help explain the widespread cellular dysfunction observed in TDP-43-associated neurodegenerative diseases, as disruptions in one pathway could potentially have cascading effects on others.