Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation

Liquid-liquid phase separation (LLPS) and subsequent liquid-gel/solid transition are considered common aggregation mechanisms of proteins linked to neurodegenerative diseases. α-synuclein (α-syn), the main factor in Parkinson's disease pathology, has been reported to undergo LLPS, thereby accelerating aggregate formation. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial. In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small compound SO286 inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation. These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.

Authors

Institutions

Publication Details

Journal
The EMBO Journal
Published
2025-10-14
DOI
https://doi.org/10.1038/s44318-025-00591-1
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation

Etsu Tashiro, Masaya Imoto, Hiroko Hirawake‐Mogi, Shinji Saiki et al.
2 citations
The EMBO Journal
RNA Research and Splicing
1.61
article

Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation

Etsu Tashiro, Masaya Imoto, Hiroko Hirawake‐Mogi, Shinji Saiki, Yoshiki Miura, Tetsushi Kataura, Daisuke Noshiro, Daisuke Taniguchi, Nobuo N. Noda, Soichiro Kakuta, Yukiko Sasazawa, Saiko Kazuno, Viktor I. Korolchuk, Seiichiro Ogawa, Mitsuhiro Kitagawa, Tomoki Takei, Tsuyoshi Saitoh, Shigeru Nishiyama, Y. Nakano, Emi Kawauchi
article en
2 citations

Abstract

Liquid-liquid phase separation (LLPS) and subsequent liquid-gel/solid transition are considered common aggregation mechanisms of proteins linked to neurodegenerative diseases. α-synuclein (α-syn), the main factor in Parkinson's disease pathology, has been reported to undergo LLPS, thereby accelerating aggregate formation. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial. In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small compound SO286 inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation. These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.

The EMBO JournalVol. 44(22)
University of Tsukuba (JP), Keio University (JP), Hokkaido University (JP), RIKEN Center for Brain Science (JP), Juntendo University (JP), Kanagawa University (JP), Modulim (United States) (US), Newcastle Hospitals - Campus for Ageing and Vitality (GB), Institute of Applied Biochemistry (JP), Daido University (JP), Newcastle University (GB), Showa Pharmaceutical University (JP)
Openalex Percentile: Top 14%
RNA Research and Splicing
1.61
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.