An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases
Authors:Sangeun Park, Sei-Kyoung Park, Peter Blair and Susan W. Liebman
Department of Pharmacology, University of Nevada, Reno, United States of America.
Keywords:
yeast, TDP-43, liquid-like droplets, metabolite-based amyloids, FRAP, metabolism disorders, ALS.
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Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Sangeun Park, Sei-Kyoung Park, Peter Blair and Susan W. Liebman (2025). An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases. Microbial Cell 12: 119-131. doi: 10.15698/mic2025.05.850
© 2025 Park et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) li-cense, which allows the unrestricted use, distribution, and repro-duction in any medium, provided the original author and source are acknowledged.
Abstract:
TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43’s effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.
doi: 10.15698/mic2025.05.850
Volume 12, pp. 119 to 131, published 22/05/2025.