An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases
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∆ ye...
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| Format: | Article |
| Language: | English |
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Shared Science Publishers OG
2025-05-01
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| Series: | Microbial Cell |
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| Online Access: | http://microbialcell.com/researcharticles/2025a-park-microbial-cell |
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| author | Sangeun Park Sei-Kyoung Park Peter Blair Susan W. Liebman |
| author_facet | Sangeun Park Sei-Kyoung Park Peter Blair Susan W. Liebman |
| author_sort | Sangeun Park |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e1df3483412b47e9b9c45b2de9f8093d |
| institution | Kabale University |
| issn | 2311-2638 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Shared Science Publishers OG |
| record_format | Article |
| series | Microbial Cell |
| spelling | doaj-art-e1df3483412b47e9b9c45b2de9f8093d2025-08-20T03:53:47ZengShared Science Publishers OGMicrobial Cell2311-26382025-05-011211913110.15698/mic2025.05.850An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseasesSangeun Park0Sei-Kyoung Park1Peter Blair2Susan W. Liebman3Department of Pharmacology, University of Nevada, Reno, United States of America.Department of Pharmacology, University of Nevada, Reno, United States of America.Department of Pharmacology, University of Nevada, Reno, United States of America.Department of Pharmacology, University of Nevada, Reno, United States of America.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.http://microbialcell.com/researcharticles/2025a-park-microbial-cellyeasttdp-43liquid-like dropletsmetabolite-based amyloidsfrapmetabolism disordersals |
| spellingShingle | Sangeun Park Sei-Kyoung Park Peter Blair Susan W. Liebman 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 yeast tdp-43 liquid-like droplets metabolite-based amyloids frap metabolism disorders als |
| title | An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| title_full | An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| title_fullStr | An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| title_full_unstemmed | An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| title_short | An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| title_sort | adenine model of inborn metabolism errors alters tdp 43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases |
| topic | yeast tdp-43 liquid-like droplets metabolite-based amyloids frap metabolism disorders als |
| url | http://microbialcell.com/researcharticles/2025a-park-microbial-cell |
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