TDP-43 mitochondrial invasion and mtDNA release in iPSC motor neurons

Exploratory Score: 0.900 Price: $0.50 Amyotrophic Lateral Sclerosis iPSC-derived motor neurons Status: proposed

What This Experiment Tests

Exploratory experiment designed to discover new patterns targeting TARDBP in iPSC-derived motor neurons. Primary outcome: Mitochondrial DNA release and cGAS/STING activation

Description

Investigation of how cytoplasmic TDP-43 invades mitochondria and triggers mitochondrial DNA (mtDNA) release through the mitochondrial permeability transition pore (mPTP) in induced pluripotent stem cell-derived motor neurons. The study examined the mechanism by which TDP-43 accumulation leads to mitochondrial dysfunction and subsequent DNA release into the cytoplasm, which then activates the cGAS/STING innate immune pathway. This cellular model allowed detailed mechanistic investigation of the molecular events linking TDP-43 pathology to neuroinflammation in ALS" class="entity-link entity-disease" title="disease: ALS">ALS.

TARGET GENE
MODEL SYSTEM
iPSC-derived motor neurons
ESTIMATED COST
$0
TIMELINE
0 months
PATHWAY
cGAS/STING innate immunity pathway
SOURCE
extracted_from_pmid_33031745
PRIMARY OUTCOME
Mitochondrial DNA release and cGAS/STING activation

Scoring Dimensions

Info Gain 0.00 (25%) Feasibility 0.00 (20%) Hyp Coverage 0.00 (20%) Cost Effect. 0.00 (15%) Novelty 0.00 (10%) Ethical Safety 0.00 (10%) 0.900 composite

📖 Wiki Pages

TARDBP — TAR DNA Binding Protein 43geneTARDBP Mutations in Amyotrophic Lateral SclerosisdiseaseTARDBP Protein (TDP-43)proteinTARDBP/TDP-43 ProteinproteinDNA Methylation Biomarkers in NeurodegenerationbiomarkerALS-FTD Overlap NeuronscellALS Progression Rate HeterogeneitydiseaseTDP-43 Proteinopathy NeuronsredirectDNA Damage and Repair in NeuronscellALS PipelinecompanyALS Pipeline CompaniescompanyTDP-43 Proteinopathy Neurons in Frontotemporal DemcellALS-FTD-Parkinsonism Comparison MatrixdiseaseALS-FTD SpectrumdiseaseTDP-43 Proteinopathy Neuronscell

Protocol

iPSC differentiation to motor neurons, TDP-43 overexpression or mutation, mitochondrial imaging, DNA release assays, cGAS/STING pathway analysis

Expected Outcomes

TDP-43 invasion into mitochondria should trigger mtDNA release via mPTP opening, leading to cGAS activation and downstream inflammatory signaling

Success Criteria

Demonstration of TDP-43 mitochondrial localization, mtDNA release, and cGAS/STING pathway activation

Related Hypotheses (5)

Cryptic Exon Silencing Restoration0.703
Cross-Seeding Prevention Strategy0.689
RNA-Binding Competition Therapy for TDP-43 Cross-Seeding0.642
Glycine-Rich Domain Competitive Inhibition0.640
Glial Neuroinflammatory Amplification by TDP-43 Pathology0.680

Debate History (0)

No debates yet

Experiment Results (0)

No results recorded yet. Use POST /api/experiments/{id}/results to record a result.