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Investigating the effect of progressive truncations at the ALS-linked protein TDP-43 RRM2 on its aggregation
Greta Grassmann1, Matteo Amadei2, Arianna Lardieri3
1Center for Life Nano and Neuro Science, Italian Institute of Technology, Rome, Italy.
Abstract:
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by inclusions of TDP-43 protein. C-terminal fragments (CTFs) of TDP-43, generated by cleavage within its second RNA recognition motif (RRM2), have been found forming aggregates in patients. Aggregation has often been attributed to the C-terminal domain, but increasing evidence indicates that RRM2 fragments contribute to pathological inclusions. We performed extensive molecular dynamics simulations to investigate the changes resulting from the truncation that could lead to aggregation. We analyzed the full RRM2 domain (fRRM2, residues 192-261) and two fragments commonly observed in CTFs (tRRM2A, residues 220-261, and tRRM2B, residues 209-261). We found that truncation results in distinct aggregation-prone states. tRRM2B appears to rely on -sheet elements associated with amyloid-like aggregation, whereas tRRM2A exhibits higher structural variability and a reduced -content, suggesting a phase separation-like aggregation mechanism. We further simulated an extended fragment of tRRM2A, tRRM2A-l (residues 220-269). Although its predicted aggregation propensity remains largely unchanged, tRRM2A-l exhibits increased structural flexibility, and a stronger exposure of Nuclear Export Signal residues. Our results indicate that subtle differences in RRM2 fragment length influence potential misfolding pathways. Future studies and therapeutic strategies to prevent TDP-43 aggregation should carefully consider the specific domain adopted.
Insights
Truncated TDP-43 protein fragments, specifically within the RRM2 domain, can adopt distinct structures promoting aggregation in amyotrophic lateral sclerosis. These findings highlight how fragment length influences misfolding pathways and aggregation mechanisms.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is linked to TDP-43 protein inclusions.
- C-terminal fragments (CTFs) of TDP-43, particularly from the RRM2 domain, contribute to pathological aggregates.
- The role of RRM2 fragments in TDP-43 aggregation is increasingly recognized.
Purpose of the Study:
- To investigate how truncation of the TDP-43 RRM2 domain influences protein aggregation.
- To analyze the structural changes and aggregation-prone states of different RRM2 fragments using molecular dynamics simulations.
- To understand the impact of fragment length on TDP-43 misfolding pathways.
Main Methods:
- Extensive molecular dynamics simulations were performed.
- Simulations analyzed the full RRM2 domain (fRRM2) and truncated fragments (tRRM2A, tRRM2B).
- Structural variability, beta-sheet content, and Nuclear Export Signal exposure were assessed.
Main Results:
- Truncation of RRM2 leads to distinct aggregation-prone states.
- tRRM2B favors amyloid-like aggregation via beta-sheet structures.
- tRRM2A shows higher structural variability and suggests a phase separation-like mechanism.
- An extended tRRM2A fragment (tRRM2A-l) displayed increased flexibility and Nuclear Export Signal exposure.
Conclusions:
- Subtle differences in RRM2 fragment length significantly impact TDP-43 misfolding pathways.
- Understanding these specific fragment behaviors is crucial for developing therapeutic strategies against TDP-43 aggregation.
- Future research and therapies should consider the specific RRM2 domain fragments involved in ALS pathology.
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