Research Articles:
Microbial Cell, Vol. 12, No. 1, pp. 119 - 131; doi: 10.15698/mic2025.05.850
An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases
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.
Received originally: 16/10/2024 Received in revised form: 16/04/2025
Accepted: 24/04/2025
Published: 22/05/2025
Correspondence:
Susan W. Liebman, Department of Pharmacology, University of Nevada, 1664 N Virginia; Mail stop 318, Reno, NV 89557; Office: 775-682-7338; Lab: 775-327-2251; FAX: 775-784-1419; sliebman@unr.edu
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
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.
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ACKNOWLEDGMENTS
We thank Robbie Joséph Loewith, Daniel J. Klionsky, Aaron Gitler, Susan Lindquist, Martin Kupiac, Dana Laor, and Ehud Gazit for the gifts of plasmids and strains, and Irina Der-katch for helpful suggestions. This work was funded by a National Institutes of Health MIRA grant (1R35GM136229-04) awarded to S.W.L. and was made possible by a grant from the National Institute of General Medical Sciences (P20GM130459) from the National Institutes of Health.
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© 2025
An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases by Park et al. is licensed under a Creative Commons Attribution 4.0 International License.
