Translocated in Liposarcoma (TLS), also known as Fused in Sarcoma (FUS), is a multifunctional RNA-binding protein implicated in neurodegenerative diseases due to its tendency to aggregate. While mutations in TLS are linked to familial amyotrophic lateral sclerosis (ALS), approximately 90% of ALS cases are sporadic with no known genetic mutations. In these instances, pathological aggregation of wild-type TLS is believed to play a critical role, although the molecular triggers remain elusive. RNA is known to modulate TLS phase separation, but the features that drive RNA-induced precipitation are poorly understood. Here, we report that synthetic PolyG RNA robustly induces both phase separation and irreversible precipitation of recombinant TLS in vitro. This effect is concentration-dependent and strongly influenced by RNA sequence composition. Specifically, guanine-rich RNAs such as PolyG promote aggregation, whereas uridine-rich RNAs fail to induce precipitation and may even inhibit it. These findings suggest a selective interaction between TLS and G-rich RNA sequences. Notably, the resulting TLS-RNA complexes undergo precipitation in a manner distinct from classical liquid-liquid phase separation, highlighting a unique mechanism of RNA-induced protein misfolding. Through detailed molecular biological and biochemical analyses, we further demonstrate that PolyG-induced condensates transition into solid-like aggregates over time. Our results uncover a previously uncharacterized pathway of RNA-mediated TLS aggregation and suggest that guanine-rich RNAs may contribute to pathological protein misfolding in neurodegenerative disease contexts.
| Published in | Biomedical Sciences (Volume 11, Issue 4) |
| DOI | 10.11648/j.bs.20251104.11 |
| Page(s) | 70-77 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2025. Published by Science Publishing Group |
TLS/FUS, ALS, Phase Separation, Poly G, RNA, IDR
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APA Style
Ueda, N., Yoneda, R., Kurokawa, R. (2025). PolyG RNA Induces Phase Separation and Precipitation of TLS/FUS. Biomedical Sciences, 11(4), 70-77. https://doi.org/10.11648/j.bs.20251104.11
ACS Style
Ueda, N.; Yoneda, R.; Kurokawa, R. PolyG RNA Induces Phase Separation and Precipitation of TLS/FUS. Biomed. Sci. 2025, 11(4), 70-77. doi: 10.11648/j.bs.20251104.11
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Download@article{10.11648/j.bs.20251104.11,
author = {Naomi Ueda and Ryoma Yoneda and Riki Kurokawa},
title = {PolyG RNA Induces Phase Separation and Precipitation of TLS/FUS},
journal = {Biomedical Sciences},
volume = {11},
number = {4},
pages = {70-77},
doi = {10.11648/j.bs.20251104.11},
url = {https://doi.org/10.11648/j.bs.20251104.11},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bs.20251104.11},
abstract = {Translocated in Liposarcoma (TLS), also known as Fused in Sarcoma (FUS), is a multifunctional RNA-binding protein implicated in neurodegenerative diseases due to its tendency to aggregate. While mutations in TLS are linked to familial amyotrophic lateral sclerosis (ALS), approximately 90% of ALS cases are sporadic with no known genetic mutations. In these instances, pathological aggregation of wild-type TLS is believed to play a critical role, although the molecular triggers remain elusive. RNA is known to modulate TLS phase separation, but the features that drive RNA-induced precipitation are poorly understood. Here, we report that synthetic PolyG RNA robustly induces both phase separation and irreversible precipitation of recombinant TLS in vitro. This effect is concentration-dependent and strongly influenced by RNA sequence composition. Specifically, guanine-rich RNAs such as PolyG promote aggregation, whereas uridine-rich RNAs fail to induce precipitation and may even inhibit it. These findings suggest a selective interaction between TLS and G-rich RNA sequences. Notably, the resulting TLS-RNA complexes undergo precipitation in a manner distinct from classical liquid-liquid phase separation, highlighting a unique mechanism of RNA-induced protein misfolding. Through detailed molecular biological and biochemical analyses, we further demonstrate that PolyG-induced condensates transition into solid-like aggregates over time. Our results uncover a previously uncharacterized pathway of RNA-mediated TLS aggregation and suggest that guanine-rich RNAs may contribute to pathological protein misfolding in neurodegenerative disease contexts.},
year = {2025}
}
TY - JOUR T1 - PolyG RNA Induces Phase Separation and Precipitation of TLS/FUS AU - Naomi Ueda AU - Ryoma Yoneda AU - Riki Kurokawa Y1 - 2025/12/17 PY - 2025 N1 - https://doi.org/10.11648/j.bs.20251104.11 DO - 10.11648/j.bs.20251104.11 T2 - Biomedical Sciences JF - Biomedical Sciences JO - Biomedical Sciences SP - 70 EP - 77 PB - Science Publishing Group SN - 2575-3932 UR - https://doi.org/10.11648/j.bs.20251104.11 AB - Translocated in Liposarcoma (TLS), also known as Fused in Sarcoma (FUS), is a multifunctional RNA-binding protein implicated in neurodegenerative diseases due to its tendency to aggregate. While mutations in TLS are linked to familial amyotrophic lateral sclerosis (ALS), approximately 90% of ALS cases are sporadic with no known genetic mutations. In these instances, pathological aggregation of wild-type TLS is believed to play a critical role, although the molecular triggers remain elusive. RNA is known to modulate TLS phase separation, but the features that drive RNA-induced precipitation are poorly understood. Here, we report that synthetic PolyG RNA robustly induces both phase separation and irreversible precipitation of recombinant TLS in vitro. This effect is concentration-dependent and strongly influenced by RNA sequence composition. Specifically, guanine-rich RNAs such as PolyG promote aggregation, whereas uridine-rich RNAs fail to induce precipitation and may even inhibit it. These findings suggest a selective interaction between TLS and G-rich RNA sequences. Notably, the resulting TLS-RNA complexes undergo precipitation in a manner distinct from classical liquid-liquid phase separation, highlighting a unique mechanism of RNA-induced protein misfolding. Through detailed molecular biological and biochemical analyses, we further demonstrate that PolyG-induced condensates transition into solid-like aggregates over time. Our results uncover a previously uncharacterized pathway of RNA-mediated TLS aggregation and suggest that guanine-rich RNAs may contribute to pathological protein misfolding in neurodegenerative disease contexts. VL - 11 IS - 4 ER -
Division of Biomedical Sciences, Saitama Medical University, Saitama, Japan
Division of Biomedical Sciences, Saitama Medical University, Saitama, Japan
Division of Biomedical Sciences, Saitama Medical University, Saitama, Japan
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