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.

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. 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
• TDP-43 Function
• Experimental Design
• Study Type
• Mechanistic Detail
• Evidence Quality

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.

• Specific Biological Pathways Involving TDP-43: If multiple pathways are mentioned, list them all. If a pathway is described but not explicitly named, summarize the description.

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.

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.

Examples:

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

Results

Characteristics of Included Studies

Study Design

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

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

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.