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, 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

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 from the Semantic Scholar corpus. 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: 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?

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. We gave the model the extraction instructions shown below for each column.

Specific Biological Pathways Involving TDP-43:

Extract all explicitly mentioned biological pathways or cellular processes that TDP-43 is involved in. Look in the methods, results, and discussion sections.

Specific areas to focus on:

RNA metabolism processes
Splicing regulation
Mitochondrial interactions
Neuronal function pathways

If multiple pathways are mentioned, list them all. If a pathway is described but not explicitly named, summarize the description.

If no clear pathways are identified, write “No specific pathways explicitly described.”

Format 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.

Search in:

Results sections describing protein interactions
Methods describing protein complex analyses
Discussion sections discussing molecular relationships

Extract:

Protein binding partners
RNA binding targets
Specific binding sites or motifs
Co-purifying proteins or complexes

If multiple interactions are found, list all. If no interactions are described, write “No molecular interactions reported.”

Format 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.

Look for:

Changes in cellular processes
Impact on gene expression
Neurological or cellular effects
Pathological consequences of interactions

Prioritize direct functional descriptions, not just descriptive observations.

If multiple consequences are found, list all. If no clear functional outcomes are described, write “No specific functional consequences reported.”

Format examples:

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

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, Amyotrophic Lateral Sclerosis (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, induced pluripotent stem cell (iPSC)-derived neurons	Nucleocytoplasmic transport	The study reported that TDP-43 aggregates disrupt nuclear pore complexes and nucleocytoplasmic transport	Yes
Chou et al., 2018	In vitro and in vivo studies	Mouse primary neurons, human fibroblasts, iPSC-derived neurons	Nucleocytoplasmic transport	The study reported that TDP-43 pathology impairs nuclear protein import and RNA export	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
Feneberg et al., 2020	In vitro and in vivo studies	Mouse primary motor neurons	Protein-protein interactions, stress response	The study reported that TDP-43 interacts with proteins involved in stress granule formation and endosomal-extracellular transport	No
Feneberga et al., “Oxidative Stress in Motor Neurons”	In vitro and in vivo studies	Mouse primary motor neurons	Protein-protein interactions, stress response	The study reported that TDP-43 mutations affect stress granule formation and extracellular vesicle secretion	No

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

The diversity of cellular models and pathways investigated highlights the multifaceted nature of TDP-43’s functions and its potential involvement in various aspects of neurodegeneration.

Based on our analysis, we identified seven primary pathways implicated in the cellular mechanisms of TDP-43:

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

These diverse pathways highlight the multifaceted role of TDP-43 in cellular function and its potential impact on various aspects of neurodegeneration.