🧫 Experiment Protocol
ExploratoryAmyotrophic Lateral SclerosisTARDBPiPSC-derived motor neuronsproposed
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.
PRIMARY OUTCOME
Mitochondrial DNA release and cGAS/STING activation
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
PROTOCOL
iPSC differentiation to motor neurons, TDP-43 overexpression or mutation, mitochondrial imaging, DNA release assays, cGAS/STING pathway analysis