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.

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

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

Specific Biological Pathways Involving TDP-43:

• RNA metabolism processes
• Splicing regulation
• Mitochondrial interactions
• Neuronal function pathways

Molecular Interactions and Binding Partners of TDP-43:

• Protein binding partners
• RNA binding targets
• Specific binding sites or motifs

Functional Consequences of TDP-43 Interactions:

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

Results

Characteristics of Included Studies

Our analysis of the 40 studies on TDP-43 pathways reveals:

• Cellular/Model Systems include diverse experimental setups.
• Pathways Investigated show TDP-43's involvement in critical cellular functions.
• Key Findings report a wide range of findings reflecting TDP-43's role in various cellular processes, including:
  • Regulation of immune response and microglial function.
  • Effects on nucleocytoplasmic transport and nuclear pore complexes.
  • Regulation of alternative splicing.

Thematic Analysis

RNA Processing and Regulation Pathways

• Describes TDP-43's multifaceted roles in RNA processing functions and related implications for cellular health.

Stress Response and Protein Quality Control Pathways

• Discusses TDP-43's impacts on stress granule dynamics and protein stability.

Synaptic Function and Neurotransmitter Pathways

• Analyzes findings related to how TDP-43 affects synaptic activity and neurotransmission regulation.

Pathway Interactions and Integration

Summarizes how TDP-43 connects with various biochemical processes underscoring its intricate role in cellular functioning and potential neurodegenerative implications.