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Updated: Oct 12, 2025
12:57
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
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FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
Pierre De Rossi1, Amanda J Lewis2, Johanna Furrer1
1Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland.
EMBO Reports
|November 22, 2021
Summary
Pathological TDP-43 aggregates in FTLD-TDP subtypes show distinct prion-like seeding properties. FTLD-TDP-A seeds amplify faster than FTLD-TDP-C seeds, correlating with disease progression and informing subtype-specific therapies.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Distinct TDP-43 aggregate morphologies characterize FTLD-TDP subtypes, but their formation and role in clinical differences are unclear.
- Evidence suggests pathological TDP-43 aggregates spread via a prion-like mechanism, yet molecular drivers remain unidentified.
Purpose of the Study:
- To compare the seeding properties of pathological aggregates from FTLD-TDP subtypes A and C.
- To investigate the mechanism of TDP-43 aggregate formation and its correlation with clinical heterogeneity.
Main Methods:
- Advanced microscopy techniques were employed to analyze patient-derived FTLD-TDP-A and FTLD-TDP-C aggregates.
- Cellular seeding models were used to assess the amplification and neoaggregation properties of these patient-derived seeds.
Main Results:
- FTLD-TDP-A seeds amplified more efficiently in a template-dependent manner than FTLD-TDP-C seeds, correlating with disease progression rates.
- Neoaggregates exhibited sequential phosphorylation with N-to-C directionality and subtype-specific timelines.
- FTLD-TDP-A neoaggregates formed large, densely packed fibrils, while FTLD-TDP-C neoaggregates were smaller and amorphous, reflecting in vivo pathology.
Conclusions:
- Cellular seeding models successfully replicate pathological diversity observed in FTLD-TDP subtypes.
- These models provide a valuable tool for developing subtype-specific therapeutics for FTLD-TDP.
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