What biological pathways is TDP-43 known to be part of?

TDP-43 functions in seven major biological pathways:

1. RNA metabolism
2. Nucleocytoplasmic transport
3. Stress response
4. Mitochondrial function
5. Synaptic function
6. Inflammatory responses
7. 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.

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?

Data extraction

• Specific Biological Pathways Involving TDP-43:

1. RNA metabolism processes
2. Splicing regulation
3. Mitochondrial interactions
4. Neuronal function pathways

• Molecular Interactions and Binding Partners of TDP-43:

1. Binds to (TG)n RNA sequences
2. Interacts with PTBP2
3. Binds mitochondrial mRNAs for ND3 and ND6

• Functional Consequences of TDP-43 Interactions:

1. Disrupts respiratory complex I assembly
2. Causes abnormal RNA splicing
3. Leads to neuronal toxicity

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

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

Pathway Interactions and Integration

Pathway Connectivity

• The Stress Response pathway was the most interconnected, being linked to 5 out of the 7 primary pathways
• Key Regulatory Points include splicing regulation, nuclear pore interactions, and stress granule dynamics.