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.

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.

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

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

No

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

No

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

Yes

Chen, 2020

Review

Various

RNA metabolism, autophagy

The review reported that TDP-43 regulates cryptic exon splicing and autophagy pathways

No

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

Yes

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

Yes

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)

Yes

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

Yes

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

No

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

No

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.

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

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
• 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
• 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

Our analysis of the pathway interactions and integration reveals:

• Pathway Connectivity:
  • The Stress Response pathway was the most interconnected, being linked to 5 out of the 7 primary pathways
  • RNA Processing was the second most interconnected pathway, connected to 4 out of the 7 primary pathways
• Key Regulatory Points:
  • Splicing regulation and mRNA stability in RNA Processing
  • Nuclear pore complex interactions in Nucleocytoplasmic Transport
  • Phase separation and stress granule dynamics in Stress Response
  • Mitochondrial mRNA binding in Mitochondrial Function
  • Receptor recycling and synaptic protein expression in Synaptic Function
  • NF-κB and NLRP3 inflammasome activation in Inflammatory Response
  • DSB repair and R-loop metabolism in DNA Repair
• Cellular Outcomes:
  • Altered gene expression and protein homeostasis
  • Disrupted RNA/protein localization and stress granule formation
  • Protein aggregation
  • Respiratory complex disruption and oxidative stress
  • Altered neurotransmission and synaptic plasticity
  • Microglial activation and neuroinflammation
  • Genome stability and cellular survival

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.