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

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

Results

Characteristics of Included Studies

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

Thematic Analysis

RNA Processing and Regulation Pathways

Our analysis 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
• Cellular Impact of TDP-43’s RNA Processing Functions:
  • Gene expression alteration was the most common impact, reported in 5 studies

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
• Cellular Impacts:
  • Stress response alteration or modulation was the most common impact, found in 4/13 studies

Synaptic Function and Neurotransmitter Pathways

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

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.