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
• 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

n = 493

Papers screened using:

• Molecular Pathway Analysis
• TDP-43 Function
• Experimental Design
• Study Type
• Mechanistic Detail
• Evidence Quality

n = 493

Papers screened out

n = 453

Papers included for extraction

n = 40

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.”

Format examples:

• RNA splicing regulation

• Mitochondrial RNA binding and respiratory complex disruption

• Synaptic function modulation

• 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.”

Format examples:

• Binds to (TG)n RNA sequences

• Interacts with PTBP2

• Binds mitochondrial mRNAs for ND3 and ND6

• 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.”

Format examples:

• Disrupts respiratory complex I assembly
• Causes abnormal RNA splicing
• Leads to neuronal toxicity

Results

Characteristics of Included Studies

Study

• Study Design
• Cellular/Model System
• Pathways Investigated
• Key Findings

Full text retrieved

• “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, induced pluripotent stem cell (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:

• Cellular/Model Systems:
  • Mouse models were the most common, used in 9 studies
  • Cultured cells were used in 6 studies
  • iPSC-derived neurons and Drosophila models were each used in 5 studies
  • 14 other cellular/model systems were used across the studies, with most appearing in 1-4 studies each
• Pathways Investigated:
  • RNA metabolism/processing was the most studied pathway, investigated in 9 studies
  • Protein interactions were examined in 5 studies
  • Mitochondrial function was studied in 4 studies
  • 7 other pathways were investigated in 2-3 studies each, including stress response, mRNA stability, RNA binding, nucleocytoplasmic transport, phosphorylation, protein aggregation, and inflammatory response
• Key Findings: The studies reported a wide range of findings, reflecting the complexity of TDP-43 function and its role in various cellular processes. Some notable findings include:
  • TDP-43’s involvement in regulating endosomal trafficking and receptor recycling
  • Its role in immune response and microglial function
  • Effects on nucleocytoplasmic transport and nuclear pore complexes
  • Regulation of alternative splicing and cryptic exon splicing
  • Involvement in stress granule formation and dynamics
  • Impact on mitochondrial function and DNA repair

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.

Thematic Analysis

RNA Processing and Regulation Pathways

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

• RNA Processing Functions:
  • Splicing regulation and RNA processing were the most common functions, each reported in 4 studies
  • mRNA stability regulation was reported in 3 studies
  • Other functions included RNA binding, autoregulation, RNA metabolism, miRNA biogenesis, and siRNA silencing
• TDP-43 RNA Targets:
  • 7 studies reported specific mRNA targets
  • 4 studies mentioned multiple mRNA or RNA targets
  • Other targets included cryptic exons, miRNAs, and retrotransposons
  • We didn’t find specific target information for 2 studies
• Cellular Impact of TDP-43’s RNA Processing Functions:
  • Gene expression alteration was the most common impact, reported in 5 studies
  • Abnormal splicing and stress granule regulation were each reported in 2 studies
  • Other impacts included transcriptome maintenance, protein isoform production, mRNA stability, exon inclusion, protein level maintenance, protein interaction, miRNA processing, retrotransposon regulation, and neurotoxicity

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

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

• Stress Response Mechanisms:
  • Stress granule-related processes were the most common mechanism, found in 6/13 studies
  • Phase separation or transition was identified in 3/13 studies
  • Other mechanisms, each found in 1 study, included autophagy, signaling regulation, general stress response, mitochondrial response, and aggresome formation
• Protein Quality Control Functions:
  • Gene regulation and mRNA stabilization were each found in 2/13 studies
  • Protein interactions were also identified in 2/13 studies
  • We found a diverse range of other functions, each in 1 study, including nuclear pore interaction, vesicle secretion, protein level regulation, RNA binding, protein homeostasis, and aggregation mechanisms
  • We didn’t find a specified function for 1 study
• Cellular Impacts:
  • Stress response alteration or modulation was the most common impact, found in 4/13 studies
  • Protein homeostasis and protein aggregation/inclusion formation were each found in 2/13 studies
  • We found a variety of other impacts, each in 1 study, including phase separation, transport alteration, communication impairment, gene expression alteration, stress granule formation and regulation, aggregation prevention, and stress response activation

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

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

• Synaptic Function:
  • We found five distinct effects, each reported in one study: regulation of receptor recycling, regulation of synaptic protein expression, binding to RNAs involved in synaptic function, regulation of dendritic complexity, and effects on axonal transport
• Neurotransmitter Regulation:
  • We found specific effects in 2/5 studies: one reported effects on ErbB4 surface delivery, and another on vesicular glutamate levels
  • We didn’t find information on neurotransmitter regulation for 3/5 studies
• Cellular Impact:
  • We found five different cellular impacts, each reported in one study: impaired trophic signaling, altered neurotransmitter release, regulation of synaptic gene expression, altered neuronal morphology, and potential impact on synaptic function and neurotransmitter release

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

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.