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Molecular mechanism of oxidation-induced TDP-43 RRM1 aggregation and loss of function
Chung-ke Chang1, Ming-hui Chiang, Elsie Khai-Woon Toh
1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Abstract:
Cysteine oxidation of the two RNA recognition motifs (RRM1 and RRM2) of TDP-43, a multi-domain protein involved in neurodegenerative diseases, results in loss of function and accumulation of insoluble aggregates under both in vitro and in vivo conditions. However, the molecular mechanisms linking cysteine oxidation to protein aggregation and functional aberration remain unknown. We report that oxidation of cysteines in RRM1, but not in other domains, induced conformational changes which subsequently resulted in protein aggregation and loss of nucleic acid-binding activity. Thus, oxidation-induced conformational change of RRM1 plays a key role in TDP-43 aggregation and disease progression.
Insights
Oxidation of the RNA recognition motif 1 (RRM1) in TDP-43 protein causes conformational changes, leading to aggregation and loss of function in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- TDP-43 protein is implicated in neurodegenerative diseases.
- Cysteine oxidation in TDP-43 leads to loss of function and aggregation.
- The molecular mechanisms linking oxidation to these effects are unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which cysteine oxidation affects TDP-43 function and aggregation.
- To identify the specific domains of TDP-43 critical for oxidation-induced changes.
Main Methods:
- In vitro and in vivo studies were conducted.
- Focus was placed on the RNA recognition motifs (RRM1 and RRM2) of TDP-43.
- Conformational changes, aggregation, and nucleic acid-binding activity were assessed.
Main Results:
- Oxidation of cysteines specifically within RRM1, not other domains, induced significant conformational changes in TDP-43.
- These oxidation-induced conformational changes directly resulted in protein aggregation.
- Loss of nucleic acid-binding activity was observed following RRM1 oxidation.
Conclusions:
- Oxidation-induced conformational changes in the RRM1 domain are a key driver of TDP-43 aggregation.
- This process is critical in the progression of TDP-43-associated neurodegenerative diseases.
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