LongeCityNews Last Updated: 03 December 2025 - 04:06 PM

The chemistry of molecules in solution is dynamic and complex, such as the spontaneous liquid-liquid phase separation in which a solution divides into regions of greater and lesser concentrations to form droplets. This process is important in the formation of protein aggregates involved in neurodegenerative disease. Here, researchers show that the α-synuclein that misfolds and aggregates to cause Parkinson's disease does not undergo liquid-liquid phase separation on its own, but rather is dragged into the liquid-liquid phase separation and droplet formation of another protein, UBQLN2. This suggests possible novel targets to interfere in this chemistry.

Some neurodegenerative disease-associated proteins form liquid droplets via liquid-liquid phase separation (LLPS). Over time, these droplets transition from a highly labile liquid state to a hydrogel state, and eventually to a solid-like condensate, via self-interaction and oligomerization of the proteins within, thereby leading to the formation of amyloid fibrils. Recently, α-synuclein (α-syn) has been reported to be one such protein. 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 molecule 1,2,3,6-tetra-O-benzoyl-muco-inositol (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.

Link: https://doi.org/10.1038/s44318-025-00591-1

Brown fat, or adipose tissue, is responsible for generating heat to maintain body temperature. Research has shown its presence and activity to be beneficial in the context of aging, in that the presence of more brown adipose improves long-term health. However, like all tissues, brown adipose tissue becomes dysfunctional with age. Here, researchers investigate what appears to be an important mechanisms in this process, in which brown fat adipocyte cells and macrophage cells of the innate immune system interact in ways that provoke inflammation and dysfunction.

Loss of brown adipose tissue (BAT) activity observed during ageing, obesity, and living at thermoneutrality is associated with lipid accumulation, fibrosis, and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances.

Mechanistically, we demonstrate that brown adipocytes secrete adenosine triphosphate (ATP) in response to imbalanced thermogenic activation, which activates the P2X4 and P2X7 receptors of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction, and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality, or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.

Link: https://doi.org/10.1038/s44319-025-00642-y

Stem cells exist in order to minimize the number of cells capable of unrestricted replication; most cells in the body are limited in the number of times that they can divide. This limit serves to reduce the risk of cancer - and other severe disruptions that could result from unlimited replication of a malfunctioning cell - to an acceptably low level to enable evolutionary success. Stem cells provide a supply of daughter somatic cells to replace those that are lost over time, due to limited somatic cell replication. In actuality, stem cells spend much of their time in a state of quiescence, without replicating. This is necessary to preserve their function and minimize damage over the course of a lifetime. When forced into excessive activity, stem cells risk a state of exhaustion, becoming dysfunctional and displaying harmful alterations in behavior.

Hematopoietic stem cells reside in the bone marrow and are responsible for generating immune cells and red blood cells. The dysfunctions that arise with aging in this cell population, such as a growing bias towards the production of myeloid cells at the expense of lymphoid cells, appear similar to the dysfunctions that arise when hematopoietic stem cells are forced into exhaustion by excessive replication. In today's open access paper, researchers explore the relevance to hematopoietic stem cell aging of IL-10 signaling intended to bring an end to an acute episode of inflammation, such as in response to an infection that is now defeated. Hematopoietic stem cells must be ever ready to produce large numbers of immune cells to help defend the body, but at the same time they must also return to quiescence when that danger is passed. The chronic inflammation of aging may well sabotage this balance, driving ever greater dysfunction in the production of immune cells.

Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are maintained in quiescence, which protects this pool from the damaging effects of excessive proliferation. Quiescence is tightly regulated by intrinsic programs, including FoxO3a, p53, and cyclin-dependent kinase inhibitors, and by extrinsic cues such as TGF-beta and Notch. Under homeostatic conditions, HSCs remain largely dormant but can rapidly activate in response to inflammatory stimuli, such as infection, to support emergency hematopoiesis. A timely return to quiescence after activation is essential to prevent stem cell exhaustion, which occurs if cycling persists.

Many hallmarks of stem cell exhaustion, including impaired regenerative capacity, expansion of phenotypic HSCs with reduced function, increased inflammatory signaling, and a shift toward myeloid-biased differentiation, mirror features of aged hematopoiesis. Aging is associated with chronic, low-grade inflammation that stresses the HSC pool, driving both functional decline and selective pressure for clones that resist inflammation-induced exhaustion.

Although much is known about maintaining HSC quiescence under steady-state conditions, the signals that govern the return to quiescence after inflammatory activation remain poorly defined. In other cell types IL-10 is an anti-inflammatory cytokine that restrains excessive immune activation by suppressing responses downstream of Toll-like receptor (TLR) stimulation. We identify IL-10 receptor (IL-10R) signaling as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Our findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis.

In a new study, the amino acid arginine shows promise in animal models of amyloid aggregation due to its ability to promote protein folding. The researchers suggest that it could be useful for early prevention and treatment of Alzheimer’s [1].

Hold it and fold it

Amino acids, the building blocks of proteins, can be potent bioactive molecules in their own right. Arginine, an amino acid abundant in foods like pumpkin and meat, has been shown to act as a chaperone, a molecule that assists in protein folding, [2] and is already used to treat several diseases. In this study, published in Neurochemistry International, researchers from Kindai University in Japan and partner institutions attempted to use this quality of arginine to tackle Alzheimer’s disease.

While scientists still don’t fully understand the etiology of Alzheimer’s, protein misfolding definitely plays a big role [3]. Misfolded amyloid beta (Aβ) protein forms fibrils and then plaques, which are Alzheimer’s most iconic hallmark, although the role of soluble Aβ may be even greater. Chaperones can sometimes inhibit misfolding of aggregation-prone proteins [4].

Preventing fibril formation

First, the researchers incubated synthetic Aβ42 peptide (the 42-amino acid form of amyloid-beta that is especially prone to aggregation) and monitored aggregation in vitro. As a positive control, they used epigallocatechin gallate (EGCG), a green tea polyphenol known to prevent amyloid aggregation [5].

Adding arginine reduced the fibril formation signal in a concentration-dependent way, up to roughly 80% inhibition at 1 mM arginine. Transmission electron microscopy (TEM) showed shorter, less developed fibrils.

Interestingly, EGCG, a ‘gold-standard’ amyloid inhibitor in vitro, was more potent than arginine. The authors, however, did not take EGCG into their fly or mouse experiments, possibly because its profile is already well explored and less drug-like: EGCG has poor oral bioavailability, binds promiscuously to many proteins, is slow to cross the blood-brain barrier, and has shown liver toxicity at therapeutic doses.

Fruit flies with human Aβ

The researchers then experimented with drosophila flies genetically modified to express human Aβ42 in the eye (a standard neurodegeneration model). Arginine reduced the fraction of cells with Aβ aggregates in a dose-dependent manner. The authors reported no change in Aβ transgene expression, meaning that arginine affected aggregation/clearance, not production. Aβ toxicity, which in this model, manifests in eye shrinkage, was reduced as well.

“Our study demonstrates that arginine can suppress Aβ aggregation both in vitro and in vivo,” explaind Prof. Yoshitaka Nagai, a senior author. “What makes this finding exciting is that arginine is already known to be clinically safe and inexpensive, making it a highly promising candidate for repositioning as a therapeutic option for AD.”

Fewer dense plaques in mice

Finally, the researchers moved to a mouse model, which carries three amyloid precursor protein (APP) mutations and is used to mimic Aβ42 plaque deposition starting around 3-4 months. These mice also develop behavioral abnormalities.

Mice received 6% arginine in drinking water starting at 5 weeks of age. This translates to a human equivalent of 940 mg/kg/day, about twice the maximum oral arginine dose currently approved in Japan for urea cycle disorders.

At 6 months (mid-stage), immunohistochemistry for Aβ showed a clear reduction in plaque area and number in the cortex and hippocampus compared to controls. However, at 9 months (near saturation of plaque load), the effect was weaker, with only a nonsignificant trend toward reduced plaque area in the hippocampus, likely because deposition was already near the ceiling. Notably, arginine-treated mice had fewer dense-core plaques than controls at both 6 and 9 months.

Insoluble Aβ42 was significantly reduced by arginine at 6 months, while soluble Aβ42 was unchanged. Like with the flies, App mRNA expression was unchanged, again arguing for an aggregation/clearance effect rather than changes in APP production.

The researchers then tested the mice’s cognitive abilities. In the Y-maze test, which assesses memory and anxiety via spontaneous alternation and locomotor activity, arginine significantly improved results at 9 months. At 6 months, however, only a weak trend toward improvement was observed, which somewhat contradicts the Aβ accumulation results.

Variability between individual mice was high, which the authors note as a possible reason for inconsistent behavioral results. However, it is also possible that the level of dense plaques, which was lower at 9 months than at 6 months, played a decisive role.

Aβ42 accumulation drives neuroinflammation, so the researchers measured mRNA levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the cortex. These were all significantly reduced in treated mice compared to controls.

A candidate for early prevention

The authors concluded that arginine behaves as a disease-modifying candidate that targets Aβ aggregation rather than just symptoms, with the benefit of being orally available, relatively cheap, and already clinically used for other indications. Because Aβ pathology begins 15 to 20 years before Alzheimer’s symptoms, they see arginine as particularly suited to long-term, preventive, or early-stage use, in contrast to expensive intravenous antibodies.

“Our findings open up new possibilities for developing arginine-based strategies for neurodegenerative diseases caused by protein misfolding and aggregation,” noted Nagai. “Given its excellent safety profile and low cost, arginine could be rapidly translated to clinical trials for Alzheimer’s and potentially other related disorders.”

Literature

[1] Fujii, K., Takeuchi, T., Fujino, Y., Tanaka, N., Fujino, N., Takeda, A., … & Nagai, Y. (2025). Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer’s disease. Neurochemistry International, 106082.

[2] Tanimoto, S., & Okumura, H. (2024). Why is arginine the only amino acid that inhibits polyglutamine monomers from taking on toxic conformations?. ACS Chemical Neuroscience, 15(15), 2925-2935.

[3] Bloom, G. S. (2014). Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, 71(4), 505-508.

[4] Liberek, K., Lewandowska, A., & Ziętkiewicz, S. (2008). Chaperones in control of protein disaggregation. The EMBO journal, 27(2), 328-335.

[5] Fernandes, L., Cardim-Pires, T. R., Foguel, D., & Palhano, F. L. (2021). Green tea polyphenol epigallocatechin-gallate in amyloid aggregation and neurodegenerative diseases. Frontiers in neuroscience, 15, 718188.