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FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models
Donovan W McDonald1, Nikita Chugh2, Rares Sava3
1Department of Biology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
BMC Biology
|February 5, 2026
Summary
Ageing and mistranslation surprisingly reduce protein aggregation in yeast models of neurodegenerative diseases. This suggests a protective role for protein aggregates in promoting longevity.
Area of Science:
- Cellular Biology
- Neuroscience
- Aging Research
Background:
- Protein aggregation is a hallmark of neurodegenerative diseases like ALS and FTD.
- Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) aggregate in neurons in ALS/FTD.
- The impact of aging and mistranslation on FUS/TDP-43 aggregation and neurotoxicity is not well understood.
Purpose of the Study:
- To investigate how aging and mistranslation affect FUS and TDP-43 aggregation.
- To explore the relationship between FUS/TDP-43 aggregation and neurotoxicity in aging.
- To utilize yeast models to study proteostasis and protein aggregation.
Main Methods:
- Developed optimized low-expression yeast models for FUS and TDP-43.
- Assessed the effects of chronological aging on proteostasis and chaperone levels.
- Investigated the impact of mistranslation (tRNA variants) on protein aggregation and cytotoxicity.
Main Results:
- Chronological aging antagonizes proteostasis, reducing chaperone levels and FUS/TDP-43 aggregation.
- Mistranslation exacerbates FUS and TDP-43 cytotoxicity.
- Aging and mistranslation synergistically impact protein aggregation and toxicity.
Conclusions:
- FUS and TDP-43 aggregation are uncoupled from toxicity under aging and mistranslation conditions.
- Protein aggregates of FUS and TDP-43 may play a protective role in promoting longevity.
- Findings offer new insights into the complex interplay between aging, mistranslation, and neurodegeneration.
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