UBQLN2 liquid droplets emerge as key catalysts of early α-synuclein aggregation

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.