Elicit: TDP-43 Biological Pathways (Public)
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:
- RNA metabolism and processing
- Nucleocytoplasmic transport
- Stress response and protein quality control
- Mitochondrial function
- Synaptic function and neurotransmitter regulation
- Inflammatory and immune responses
- 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.
Results
Characteristics of Included Studies
| Study | Study Design | Cellular/Model System | Pathways Investigated | Key Findings |
|---|---|---|---|---|
| “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, ALS patient-derived microglia | Immune response, phagocytosis | Targeting TDP-43 C-terminal domain reduces pathology and enhances microglial function |
| Ayala et al., 2008 | In vitro study | Human cells | Cell cycle regulation | TDP-43 regulates Cyclin-dependent kinase 6 (Cdk6) expression and cell cycle progression |
| Chen, 2020 | Review | Various | RNA metabolism, autophagy | TDP-43 regulates cryptic exon splicing and autophagy pathways |
| Chou et al., 2017 | In vitro and in vivo studies | Mouse primary neurons, human fibroblasts, iPSC-derived neurons | Nucleocytoplasmic transport | 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 | 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 | 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 | TDP-43 mutations affect RNA processing and axonal transport |
Our analysis of the 40 studies on TDP-43 pathways reveals significant pathways implicated in the cellular mechanisms of TDP-43:
- Cellular/Model Systems: Mouse models were the most common, used in 9 studies.
- Pathways Investigated: RNA metabolism/processing was the most studied pathway, investigated in 9 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, including endosomal trafficking and receptor recycling, immune response, nucleocytoplasmic transport, splicing regulation, and stress granule dynamics.
Thematic Analysis
RNA Processing and Regulation Pathways
| Study | RNA Processing Function | Specific Targets/Mechanisms | Cellular Impact |
|---|---|---|---|
| Chen, 2020 | Cryptic exon splicing regulation | Repression of cryptic exons | Maintenance of normal transcriptome |
| Deshaies et al., 2018 | Alternative splicing regulation | hnRNP A1 pre-mRNA | Production of aggregation-prone hnRNP A1B isoform |
| Fazal et al., 2021 | RNA processing, splicing regulation | Various mRNA targets | Altered gene expression in motor neurons |
The analysis suggests TDP-43 involves various RNA processing functions, notably splicing regulation and mRNA stability regulation, with significant cellular impacts.
Stress Response and Protein Quality Control Pathways
| Study | Stress Response Mechanism | Protein Quality Control Function | Cellular Impact |
|---|---|---|---|
| Chen, 2020 | Autophagy regulation | Regulation of ATG7 and other autophagy-related genes | Maintenance of cellular protein homeostasis |
| Chou et al., 2017 | Stress granule dynamics | Interaction with nuclear pore complexes | Altered nucleocytoplasmic transport under stress |
| Feneberg et al., 2020 | Stress granule formation | Interaction with stress granule proteins | Altered stress response under oxidative conditions |
TDP-43's role in cellular stress responses emphasizes stress granule dynamics and phase separation processes, which significantly affect cellular functions.
Synaptic Function and Neurotransmitter Pathways
| Study | Synaptic Function | Neurotransmitter Regulation | Cellular Impact |
|---|---|---|---|
| “TDP‐43 Loss of Function,” 2016 | Regulation of receptor recycling | Affects ErbB4 surface delivery | Impaired trophic signaling |
| Heyburn and Moussa, 2016 | Regulation of synaptic protein expression | Affects vesicular glutamate levels | Altered neurotransmitter release |
Diverse effects of TDP-43 on synaptic function highlight its importance across multiple pathways related to neuronal function and neurotransmission.
Pathway Interactions and Integration
| Primary Pathway | Connected Pathways | Regulatory Points | Cellular Outcomes |
|---|---|---|---|
| RNA Processing | Stress Response, Synaptic Function | Splicing regulation, mRNA stability | Altered gene expression, protein homeostasis |
| Nucleocytoplasmic Transport | RNA Processing, Stress Response | Nuclear pore complex interactions | Disrupted RNA/protein localization, stress granule formation |
This analysis reveals interconnections between multiple pathways involving TDP-43, suggesting its multifaceted cellular functions and possible implications in neurodegenerative diseases.