TDP-43 is intercellularly transmitted across axon terminals

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Transactive response DNA-binding protein 43 kD (TDP-43) aggregates in amyotrophic lateral sclerosis (ALS).
• TDP-43 oligomers are hypothesized to spread between cells, explaining ALS symptom progression.
• Prion-like behavior of TDP-43 is implicated in neurodegenerative diseases.

Purpose of the Study:

• To develop a novel assay for quantifying TDP-43 oligomers in living cells.
• To investigate the intercellular transmission mechanisms of TDP-43.
• To explore the role of TDP-43 in ALS pathogenesis and symptom spreading.

Main Methods:

• Developed a novel protein complementation assay for TDP-43 oligomer quantification.
• Utilized microfluidic neuronal cultures for studying synaptic spreading.
• Analyzed TDP-43 in microvesicles/exosomes from cultured cells and ALS patient brain lysates.

Main Results:

• Demonstrated TDP-43 exchange between cell somata and its presence in microvesicles/exosomes.
• Showed preferential uptake and higher toxicity of microvesicular TDP-43 in recipient cells.
• Provided evidence for anterograde and retrograde trans-synaptic spreading of TDP-43.
• Confirmed TDP-43 oligomer seeding using cell-derived and patient-derived material.

Conclusions:

• TDP-43 spreads intercellularly via microvesicles, with preferential uptake by recipient cells.
• Synaptic transmission (anterograde and retrograde) and prion-like seeding of TDP-43 contribute to ALS progression.
• The novel assay facilitates further research into TDP-43 oligomerization and propagation in ALS.