Elicit: TDP-43 Biological Pathways (Public)
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, 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:
- 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.
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.
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
| 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, 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, iPSC-derived neurons | Nucleocytoplasmic transport | The study reported that TDP-43 aggregates disrupt nuclear pore complexes and nucleocytoplasmic transport | 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 |
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
- 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
- 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
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
- Other functions included RNA binding, autoregulation, RNA metabolism, miRNA biogenesis, and siRNA silencing
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
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.