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Probing TDP-43 condensation using an in silico designed aptamer
Elsa Zacco1, Owen Kantelberg2, Edoardo Milanetti3,4
1Centre for Human Technologies (CHT), Istituto Italiano di Tecnologia (IIT), Via Enrico Melen, 83, 16152, Genova, Italy.
Nature Communications
|June 23, 2022
Summary
Researchers designed novel aptamers to visualize protein aggregates linked to Amyotrophic Lateral Sclerosis. These aptamers successfully tracked TAR DNA-binding protein 43 (TDP-43) oligomers using super-resolution microscopy, offering new insights into disease mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Aptamers are artificial oligonucleotides with therapeutic and diagnostic potential.
- Designing aptamers for specific molecular targets remains challenging.
- TDP-43 aggregation is implicated in Amyotrophic Lateral Sclerosis (ALS).
Purpose of the Study:
- To generate aptamers targeting TDP-43 using the catRAPID algorithm.
- To utilize these aptamers for visualizing TDP-43 assemblies, including those below the diffraction limit of light.
- To investigate TDP-43 phase transitions in cellular models.
Main Methods:
- Exploitation of the catRAPID algorithm for de novo aptamer generation.
- Characterization of aptamer binding affinity to TDP-43.
- Application of super-resolution microscopy with aptamer probes for visualization.
- In-cell studies to observe TDP-43 interactions with aptamers.
Main Results:
- Successfully generated aptamers targeting TDP-43.
- Identified Apt-1 as a high-affinity interactor for TDP-43.
- Visualized TDP-43 oligomers at 10 nm resolution using Apt-1 and super-resolution microscopy.
- Demonstrated Apt-1 interaction with both diffuse and condensed TDP-43 forms in cells.
Conclusions:
- De novo aptamer generation is a viable strategy for targeting proteins like TDP-43.
- Aptamers can serve as effective probes for super-resolution microscopy of protein condensates.
- This approach enables the study of protein phase transitions and dynamics in diseases like ALS.
