Parkinson's disease (PD) is an age-related, progressive neurodegenerative disorder. The hallmark of PD pathogenesis is the Lewy bodies (LBs) that accumulate in neurons in the substantia nigra region of the brain, damaging these neurons and leading to the motor symptoms of the disease. α-synuclein (α-syn), a misfolded protein, aggregates and forms fibrils, which leads to the formation of LBs. The exact molecular mechanism behind this aggregation process is yet to be uncovered. With an increasing number of elderly patients suffering from Parkinson's and other neurodegenerative diseases worldwide, it is important to understand the aggregation process, find potential therapeutic targets to mitigate or inhibit the aggregation, and slow down the disease progression.
Liquid-liquid phase separation (LLPS), a process where a uniform mixture spontaneously divides into two liquid phases with differing component concentrations, is often considered the reason behind α-syn aggregation. Even though LLPS of α-syn was previously reported, the question remains: are they involved in catalyzing the early stage of aggregation? Ubiquilin-2 (UBQLN2) protein, mainly involved in maintaining protein homeostasis, also undergoes LLPS under certain physiological conditions. Interestingly, it is known to be associated with several neurodegenerative diseases.
Are liquid droplets formed by UBQLN2 catalyzing the α-syn protein aggregation? A team of researchers from Juntendo University Faculty of Medicine, Japan, led by Professor Masaya Imoto, Professor Nobutaka Hattori, Dr. Tomoki Takei and Dr. Yukiko Sasazawa, decided to unravel the involvement of UBQLN2 in α-syn aggregation and fibril formation. "By uncovering the mechanisms that trigger the aggregation process, we hope to find new ways to prevent it and ultimately contribute to the development of disease-modifying treatments," mentioned Prof. Imoto while talking about the motivation behind this study. The study was made available online on October 14, 2025, and published in Volume 44, Issue 22 of The EMBO Journal on November 17, 2025
The study involved methods to understand protein–protein interactions. Both proteins were given fluorescent labeling, and microscopic techniques were involved. SH-SY5Y cell line was used for in vitro studies. Brain sections from patients with sporadic PD were also studied to see the localization of UBQLN2.
The study confirmed the incorporation of α-syn in the UBQLN2 LLPS. Each protein has multiple domains or regions, and they are involved in different functions. Identifying the domain involved in the interaction is important as it helps in developing therapeutic strategies. α-syn primarily interacts with STI1 regions of UBQLN2. "The STI1-2 domain of UBQLN2 directly interacts with α-syn, facilitating α-syn aggregation within UBQLN2 condensates," explained Dr. Sasazawa. The researchers discovered the presence of UBQLN2 in the substantia nigra region of brain sections collected from patients with sporadic PD. This confirmed its involvement in α-syn aggregation and fibril formation.
The researchers also wanted to find out if 1,2,3,6-tetra-O-benzoyl-muco-inositol (SO286) plays a role in preventing the α-syn aggregation. The compound was found to interact with UBQLN2, preventing its self-association and liquid droplet formation. The compound interestingly binds to the same region that is involved in UBQLN2 and α-syn interaction. When the compound interacts with UBQLN2, its interaction with α-syn is prevented, minimizing the α-syn aggregation process.
A cure for PD is yet to be discovered, and for now, the existing treatment plans revolve around alleviating the symptoms. As this is a progressive neurodegenerative disorder, it is important to find a way to minimize the aggregation and slow down the LB deposition in the brain. The researchers have finally discovered a novel mechanism underlying the aggregation of α-syn. This can open the door to new treatments for PD and other related disorders. "Our study points towards a promising therapeutic approach for neurodegenerative diseases. Compounds that block the fibril-catalyzing activity of proteins like UBQLN2 could be developed into drugs, which can lead to preventing harmful aggregate formation," concluded Prof. Hattori.
Reference
Authors |
Tomoki Takei1,2, Yukiko Sasazawa1,2,3,4, Daisuke Noshiro5, Mitsuhiro Kitagawa1,2, Tetsushi Kataura2,6, Hiroko Hirawake-Mogi1, Emi Kawauchi2, Yuya Nakano2, Etsu Tashiro2,11, Tsuyoshi Saitoh7,12, Shigeru Nishiyama7, Seiichiro Ogawa2, Soichiro Kakuta8, Saiko Kazuno8, Yoshiki Miura8, Daisuke Taniguchi1, Viktor I Korolchuk9, Nobuo N Noda5, Shinji Saiki1,4,6, Masaya Imoto1,2,4,and Nobutaka Hattori1,3,4,10 |
Title of original paper |
Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation |
Journal |
The EMBO Journal |
DOI |
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Affiliations |
1Department of Neurology, Juntendo University Faculty of Medicine, Japan 2Department of Biosciences and Informatics, Keio University, Kanagawa, Japan 3Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Japan 4Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Japan 5Institute for Genetic Medicine, Hokkaido University, Japan 6Department of Neurology, Institute of Medicine, University of Tsukuba, Japan 7Department of Chemistry, Keio University, Japan 8Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Japan 9Biosciences Institute, Faculty of Medical Sciences, Campus for Ageing and Vitality, Newcastle University, UK 10Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Japan 11Present address: Laboratory of Biochemistry, Showa Pharmaceutical University, Japan 12Present address: Institute of Medicine, University of Tsukuba, Japan |
About Professor Masaya Imoto from Juntendo University Faculty of Medicine, Japan
Prof. Masaya Imoto is associated with the Department of Neurology and the Division for Development of Autophagy Modulating Drugs of Juntendo University Faculty of Medicine, Japan. His present research work focuses on different aspects of Parkinson's disease. Prof. Imoto has authored over 200 research articles to date. He has obtained a substance patent for the novel tyrosine kinase inhibitors. He has received multiple awards, including the Japan Society for Bioscience, Biotechnology, and Agrochemistry Award for Senior Scientists in 2018.
About Professor Nobutaka Hattori from Juntendo University Faculty of Medicine, Japan
Prof. Nobutaka Hattori is the Professor of the Department of Neurology at Juntendo University. He earned his Ph.D. from the same institution in 1994. Prof. Hattori's research focuses on elucidating the molecular mechanisms underlying neurodegenerative diseases, particularly Parkinson's disease, with the goal of developing novel diagnostic tools and therapeutic strategies. A recipient of many prizes, including the Takeda Prize for Medical Science and, more recently, the prestigious Japan Academy Prize, he has authored more than 1000 peer-reviewed publications to date. Prof. Hattori and his collaborators were the first to identify the "parkin" gene, which is associated with the onset of familial Parkinson's disease.
About Associate Professor Yukiko Sasazawa from Juntendo University Faculty of Medicine, Japan
Dr. Yukiko Sasazawa is currently affiliated with Juntendo University. She obtained her Ph.D. from Keio University in 2012. Her research focuses on the molecular mechanisms of neurodegenerative diseases, with particular emphasis on the discovery of Parkinson's disease therapeutics targeting cellular environments that promote α-synuclein degradation. Dr. Sasazawa has authored about 40 research articles, which have collectively received more than 1,200 citations. She has received multiple honors, including Morita Science Research Encouragement Prize, Japan Association of University Women (JAUW).
About Tomoki Takei from Juntendo University Faculty of Medicine, Japan
Dr. Tomoki Takei is currently affiliated with Nippon Shinyaku Co., Ltd. From 2021, he was a doctoral student in the Graduate School of Medicine at Juntendo University, where he completed his Ph.D. in Medicine in 2025. His doctoral research focused on elucidating the pathogenic mechanisms underlying Parkinson's disease and analyzing the mode of action of seed compounds for therapeutic drug development. He received the Poster Award at the 24th Annual Meeting of the Japanese Association for Molecular Target Therapy of Cancer in 2020.
