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: 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:

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:

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
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., 2016 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

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
Stress Response RNA Processing, Protein Quality Control Phase separation, stress granule dynamics Altered stress granule assembly, protein aggregation
Mitochondrial Function Stress Response, DNA Repair Mitochondrial mRNA binding Respiratory complex disruption, oxidative stress
Synaptic Function RNA Processing, Protein Quality Control Receptor recycling, synaptic protein expression Altered neurotransmission, synaptic plasticity
Inflammatory Response Stress Response, Mitochondrial Function NF-κB and NLRP3 inflammasome activation Microglial activation, neuroinflammation
DNA Repair RNA Processing, Stress Response Double-Strand Break repair Genome stability, cellular survival