bims-proned 2025-12-21 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–12–21
fourteen papers selected by
Verena Kohler, Umeå University

Unfolding Sequence-Specific Enigma in Monomeric α-Synuclein: Implications for Parkinson's Disease.
Interplay between lipid droplets and alpha-synuclein: implication in Parkinson's disease pathogenesis.
RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery.
Optogenetic-induced α-synuclein accumulation reveals early synaptic dysfunction in experimental models of Parkinson's disease.
The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.
Familial mutations modulate α-synuclein interactions with key neuronal membrane lipids.
GM1 and OligoGM1 Drive Divergent α-Synuclein Aggregation Pathways.
Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.
Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.
Epitope-specific antibodies can distinguish between soluble huntingtin exon-1 and its diverse cellular aggregates.
Inertial Agitation in an NMR Magnet: Real-Time Monitoring of Protein Aggregation at High Resolution.
Protein aggregates and biomolecular condensates: implications for human health and disease.
Protein quality control: from molecular mechanisms to aging and disease - EMBO workshop, May 18-23, 2025, Hersonissos, Greece.
Modulation of Liquid-to-Solid Phase Transition in Coacervates for Neurodegenerative Disease Treatments.

ACS Chem Neurosci. 2025 Dec 18.

Unfolding Sequence-Specific Enigma in Monomeric α-Synuclein: Implications for Parkinson's Disease.

Priyatosh Ranjan, Ashutosh Kumar.

  Parkinson's disease (PD) is a debilitating neurological disorder characterized by the buildup of abnormal protein clumps, primarily composed of a protein called Alpha-Synuclein (α-Syn). Under physiological conditions, α-Syn exists as a dynamic, intrinsically disordered protein that resists aggregation through transient intramolecular interactions. However, under pathological conditions, this protein can misfold and stack into rigid, fibrous structures known as amyloid fibrils. These fibrillar deposits accumulate within neurons and are central to PD pathogenesis. This review focuses on understanding what keeps monomeric α-Syn in its innocuous form and what causes it to shift into a disease-associated state. In particular, we explore the role of subtle, often-overlooked intramolecular forces, like cation-π, π-π, and CH-π interactions, that may help stabilize the protein and prevent aggregation. We also examine how genetic mutations linked to familial forms of PD influence these internal interactions and drive the formation of partially folded intermediate forms that can trigger fibril growth. Some familial mutations accelerate α-Syn aggregation, while others slow it down, but the reasons behind these different outcomes are not fully understood. By analyzing how these mutations alter the protein's early structure and behavior, this review aims to shed light on the first steps of α-Syn misfolding. A deeper understanding of these mechanisms could support the development of new therapies designed to stabilize the soluble form of monomeric α-Syn and slow or prevent disease progression.

Keywords:  Lewy body; Parkinson’s disease; amyloid fibril; familial mutations; intramolecular contacts; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00423
Front Mol Neurosci. 2025 ;18 1681039

Interplay between lipid droplets and alpha-synuclein: implication in Parkinson's disease pathogenesis.

Walid Idi, Razan Sheta, Abid Oueslati.

  Lipid droplets (LDs), once considered inert lipid stores, are now recognized as active regulators of lipid metabolism, stress responses, and protein quality control in the brain. Their dysregulation is increasingly linked to neurodegenerative diseases, notably Parkinson's disease (PD). This review explores the emerging bidirectional relationship between LDs and α-synuclein (α-Syn), a key pathological hallmark of PD. α-Syn can promote LD accumulation by modulating lipid metabolism and inhibiting lipolysis, while LDs can facilitate α-Syn aggregation through specific lipid-protein and membrane interactions. We summarize current evidence on LD structure, function, and dynamics in neuronal and glial cells, and discuss how alterations in lipid composition, oxidative stress, and associated proteins contribute to PD pathology. Understanding the LD-α-Syn interplay reveals new avenues for therapeutic strategies aimed at restoring lipid homeostasis, enhancing LD turnover, and reducing α-Syn toxicity.

Keywords:  Parkinson’s disease; alpha-synuclein; lipid droplet functions; lipid droplets; lipid metabolism; lipid-alpha-synuclein interaction; protein aggregation

DOI:  https://doi.org/10.3389/fnmol.2025.1681039
J Pharmacol Sci. 2026 Jan;pii: S1347-8613(25)00110-0. [Epub ahead of print]160(1): 64-68

RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery.

Yasushi Yabuki, Norifumi Shioda.

  Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol-gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.

Keywords:  Liquid-liquid phase separation; Neurodegenerative disorders; Prion-like proteins; RNA G-quadruplex; Sol-gel transition

DOI:  https://doi.org/10.1016/j.jphs.2025.11.006
NPJ Parkinsons Dis. 2025 Dec 13.

Optogenetic-induced α-synuclein accumulation reveals early synaptic dysfunction in experimental models of Parkinson's disease.

Raquel Rodriguez-Aller, Beatriz Romero-Quineche, Marc Morissette, Razan Sheta, Thérèse Di Paolo, Armen Saghatelyan, Abid Oueslati.

Presynaptic accumulation of misfolded α-synuclein (α-syn) and altered synaptic transmission are considered early events in the pathogenesis of Parkinson's disease (PD), suggesting a potential causal link between these two events. However, the mechanisms by which α-syn aggregation induces synaptic dysfunction and the subsequent progressive neurodegeneration remain elusive. In the present study we leveraged the high temporal resolution of the Light-Inducible Protein Aggregation (LIPA) system in vivo and in human dopaminergic neurons to explore the early sequence of α-syn-induced pathological events leading to synaptopathy. We observed that nigrostriatal axonal transport and presynaptic accumulation of α-syn aggregates altered the activity of different neuronal populations in the mouse striatum. The results of histological and metabolite analyses show that presynaptic accumulation of α-syn induced a shift in the activation pattern of D1- and D2-expressing striatal medium spiny neurons, caused an increase in the size and density of dopaminergic synapses, and disrupted striatal dopamine signaling. Altogether, our findings reveal that the accumulation of α-syn in dopaminergic terminals triggered early presynaptic impairments, which subsequently altered striatal neuronal activity. Our study provides new insights into the molecular mechanisms underlying early synaptopathy in PD.

DOI: https://doi.org/10.1038/s41531-025-01201-x
Front Aging Neurosci. 2025 ;17 1730206

The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.

Shanshan Jia, Quan Li, Xue Rui, Wen Qin, Wenhui Zhang, Jinjin Dou, Xiwu Zhang.

  Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; current therapies can neither cure AD nor prevent its progression. The pathological hallmark of AD is the excessive deposition of abnormal proteins in the brain, primarily including β-amyloid (Aβ) and phosphorylated Tau proteins. The ubiquitin-proteasome system (UPS), a central intracellular protein degradation mechanism that removes misfolded proteins and maintains cellular homeostasis by inhibiting aberrant protein aggregation, plays an important role in the regulation of various physiological functions, as well as in the development of disease. Any abnormality in this process leads to protein misfolding and aggregation, and the accumulation and aggregation of ubiquitinated proteins is a common feature of many neurodegenerative diseases, including AD. A growing number of studies have confirmed the significance of UPS in the AD process, which may act in conjunction with other mechanisms leading to the development of AD, and may even be the direct cause of AD. UPS offers a whole new possibility for the development of drugs for AD prevention and treatment, as well as new strategies and approaches for the treatment of neurodegenerative diseases. Therefore, this review is based on UPS, describes the possible mechanisms of action of UPS in AD, and summarizes the preclinical studies of modulating UPS for the treatment of AD.

Keywords:  Alzheimer’s disease; Aβ protein; tau protein; ubiquitin-proteasome system; ubiquitination

DOI:  https://doi.org/10.3389/fnagi.2025.1730206
FEBS J. 2025 Dec 15.

Familial mutations modulate α-synuclein interactions with key neuronal membrane lipids.

Abid Ali, Mikhail Matveyenka, Dmitry Kurouski.

  Progressive aggregation of α-synuclein (α-Syn) in the midbrain, hypothalamus and thalamus is linked to Parkinson's disease (PD), one of the fastest growing neurodegenerative diseases in the U.S. Studies of families with PD history revealed several mutations that are responsible for the early-onset (A30P, E46K, A53T) and late-onset (H50Q) forms of PD. A growing body of evidence indicates that phospho-/sphingolipids and cholesterol alter the aggregation properties of wild-type (WT) α-syn. However, the effects of these lipids on the rate of α-syn mutants remain unclear. In the current study, we determined the aggregation rates of A30P, E46K, A53T, H50Q and WT α-syn in the presence of large unilamellar vesicles composed of phosphatidylcholine (PC), sphingomyelin (SM) and cholesterol (Cho)-the key lipids of neuronal membranes. We also utilised a set of biophysical methods to reveal the extent to which lipids alter the morphology and secondary structure of amyloid fibrils. We found that familial mutations uniquely altered α-syn interactions with lipid bilayers, which resulted in the altered rate of protein aggregation in the presence of lipid bilayers. Furthermore, A30P mutation fully disabled α-syn interaction with LUVs, while E46K, A53T and H50Q mutations altered cytotoxicity of α-syn fibrils formed in the presence of lipid bilayers. These results suggest that changes in plasma membrane lipid profiles may have a strong effect on the onset and progression of PD in individuals with familial mutations.

Keywords:  cholesterol; fibrils; phosphatidylcholine; sphingomyelin; toxicity; α‐Synuclein

DOI:  https://doi.org/10.1111/febs.70363
Langmuir. 2025 Dec 13.

GM1 and OligoGM1 Drive Divergent α-Synuclein Aggregation Pathways.

Cecilia Vasti, María Elisa Mariani, Mónica S Sánchez, Pablo E A Rodríguez, Gerardo D Fidelio.

Parkinson's disease (PD) is an age-related disorder characterized by amyloid deposits of the 140-amino-acid protein α-synuclein (AS), which contribute to neuronal dysfunction and degeneration, leading to motor and cognitive impairments. AS fibrillation, the process by which the native soluble protein misfolds into insoluble cross-β-sheet fibrils, involves transient prefibrillar species with distinct biophysical features. In vitro evidence suggests that these oligomeric intermediates, rather than mature fibrils, are the primary pathogenic agents in neurodegenerative diseases. Initial studies demonstrated that AS fibril formation is inhibited upon binding to lipid vesicles containing GM1 ganglioside. Here, we report for the first time the effect of the oligosaccharide portion of GM1 on AS fibrillation under in vitro conditions. To assess the specific contribution of this hydrophilic headgroup, we synthesized the oligosaccharide moiety of GM1 (oligoGM1) and compared its effect with that of GM1 micelles. We show that oligoGM1 stimulates amyloid fibril formation, whereas GM1 reduces or inhibits AS aggregation in a lipid/protein ratio-dependent manner. AFM analysis revealed that fibrils formed in the presence of oligoGM1 were lower in height than control fibrils, and that structures compatible with AS oligomers accumulated in the presence of GM1. Using dot blotting and AFM, we further confirmed that GM1 promotes the formation of oligomeric AS species in vitro. ThT-based aggregation kinetics showed that AS aggregation in the presence of GM1 was markedly slower than with oligoGM1, supporting that oligoGM1 accelerates AS fibrillation. Finally, cytotoxicity assays in SH-SY5Y neuroblastoma cells demonstrated that oligomers generated in the presence of GM1 exhibited higher toxicity than AS fibrils formed in the absence or presence of oligoGM1. These findings highlight the importance of the hydrophobic lipid moiety of GM1 in modulating AS aggregation and support the emerging view that the extent of fibrillar amyloid deposition does not correlate directly with neurodegenerative disease pathogenesis.

DOI: https://doi.org/10.1021/acs.langmuir.5c04731
Cell Death Differ. 2025 Dec 14.

Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.

Qinyu Peng, Guoxin Zhang, Xiaodi Guo, Xu Xu, Yiming Li, Lina Pan, Lanxia Meng, Jing Xiong, Sheng Li, Zhentao Zhang.

Parkinson's disease (PD) is characterized by the aggregation of misfolded α-synuclein (α-syn) and microglial activation. Galectin-9 (Gal-9) is an immunoregulatory mediator generated by microglia. Here, we found that α-syn fibrils are internalized by microglia and processed by microglial protease AEP, generating α-syn species with enhanced seeding activity and neurotoxicity. Notably, the uptake of α-syn fibrils by microglia leads to increased expression of Gal-9, which further promotes the production of toxic α-syn species via activation of the C/EBPβ/AEP axis. Knockout of Gal-9 attenuates α-syn pathology, dopaminergic neuronal loss, and motor impairments in a mouse model induced by intrastriatal injection of α-syn PFFs. Intrastriatal injection of Gal-9 promoted PD-like phenotypes induced by α-syn PFFs. Furthermore, the detrimental effect of Gal-9 was attenuated by the knockout of AEP. These observations illustrate the key role of Gal-9 in promoting α-syn pathology and neurodegeneration via the C/EBPβ/AEP axis in PD.

DOI: https://doi.org/10.1038/s41418-025-01640-2
Neurochem Int. 2025 Dec 11. pii: S0197-0186(25)00176-7. [Epub ahead of print]192 106103

Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.

Huahua Shi, Yan Zhao.

  Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau4RDΔK280 cells while reducing the amount of tau4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau4RDΔK280 cells by preventing the formation of tau4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.

Keywords:  Alzheimer's disease; Astaxanthin; Protein aggregation; tau(4RD)ΔK280

DOI:  https://doi.org/10.1016/j.neuint.2025.106103
J Biol Chem. 2025 Dec 12. pii: S0021-9258(25)02900-X. [Epub ahead of print] 111048

Epitope-specific antibodies can distinguish between soluble huntingtin exon-1 and its diverse cellular aggregates.

Joshua Lugo, Hui Xu, Jeannie Chen, Ali Khoshnan, Ralf Langen.

  Misfolding and aggregation of huntingtin exon-1 (Httex1) with an expanded polyglutamine region is a key pathological hallmark of Huntington's disease (HD), making conformationally specific Httex1 binders potentially valuable diagnostic or therapeutic tools. To define epitopes, which might confer conformationally specific Httex1 binding, we characterized five newly developed huntingtin antibodies (PHP5- PHP9). Binding to recombinant proteins as well as staining of HEK293 cells and R6/1 mice shows that PHP5 and PHP6 preferentially bind monomers over fibrils. Using EPR, peptide arrays, and deletion mutants, we mapped binding of PHP5 and PHP6 to the hydrophobic surface of an N-terminal α-helix spanning residues 4 to 18 of Httex1. In contrast, PHP7, PHP8, and PHP9, raised against protofibrils, recognize proline repeats within the C-terminal proline rich domain (PRD). These antibodies showed a preference for aggregates in cells, but neither the N-terminal N17 region nor the polyQ fibril-forming core region was required. Similar fibril binding was also observed with an α-synuclein-PRD chimera, where the PRD was fused to the fibril-forming core of α-synuclein. Thus, a high density of PRD regions, rather than fibril core features, are needed for fibril binding. Interestingly, all PRD binding antibodies, including PHP1 and P90, preferentially bound aggregates, but recognition of different cellular aggregates varied, revealing heterogeneity both within aggregates (rim vs. interior) and between aggregates. Together, the binding principles uncovered here could serve as a basis for the design and optimization of binders with potential diagnostic or therapeutic relevance.

Keywords:  Huntington disease; antibody; biomarker; electron paramagnetic resonance; polyglutamine; protein aggregation

DOI:  https://doi.org/10.1016/j.jbc.2025.111048
J Am Chem Soc. 2025 Dec 15.

Inertial Agitation in an NMR Magnet: Real-Time Monitoring of Protein Aggregation at High Resolution.

Jongchan Lee, Sohyun Jung, Seungjoon Yu, Sho Hee Park, Nak-Kyoon Kim, Jung Ho Lee.

We present a simple and efficient method to agitate NMR samples and thereby induce protein aggregation directly inside an NMR magnet. In this approach, termed inertia NMR, the rotational inertia of an eccentric floater within the sample tube generates agitation during acceleration and deceleration of tube spinning. This method enabled the aggregation of multiple disease-associated proteins under near-physiological conditions while allowing real-time monitoring by NMR spectroscopy. By combining inertia NMR with 2D NMR, we followed the aggregation of an α-synuclein (αS) isoform at high resolution. In addition, isotope editing/filtering in the presence of inertial agitation allowed individual tracking of protein coaggregation. Remarkably, αS aggregation was accelerated by its splicing isoform and even more strongly by the C-terminal domain of TDP-43 (TDP-43 CTD), underscoring the role of cross-seeding in synucleinopathies. Furthermore, inertia NMR demonstrated diagnostic potential by discriminating Parkinson's disease from multiple system atrophy using patient-derived seeds. This method provides high-resolution insight into protein aggregation and offers a general, instrument-free strategy to accelerate chemical processes inside an NMR magnet through efficient sample mixing.

DOI: https://doi.org/10.1021/jacs.5c16918
Front Mol Biosci. 2025 ;12 1719678

Protein aggregates and biomolecular condensates: implications for human health and disease.

Ambuja Navalkar, Anoop Arunagiri, Tovaria Kee, Kathigna Panchal, Kathryn Dick.

  Biomolecular condensates are at the forefront of understanding biological concepts, representing one of the most revolutionary areas in cell biology over the last decade. Numerous proteins, peptides, and nucleic acids have been shown to form membrane-less organelles, also known as condensates, in cells, demonstrating their functional relevance. Multiple research approaches in the fields of physics, chemistry, and biophysics investigate the underlying multivalent interactions that influence the phase separation of biomolecules. As failure to regulate condensate properties, such as formation and/or dissolution has been postulated as a driver of the misfolding and aggregation of proteins in stress, aging, and neurodegeneration disorders, understanding the fundamentals of condensate assembly has been considered of utmost importance. In this review, we will focus on the key regulators and biophysical drivers of phase separation and protein aggregation, evidenced in the literature. We will elaborate on the dynamic interplay between phase separated and aggregated state, highlighting the emergent properties of condensates that can contribute to the misfolding of proteins in the context of physiology and diseases. An in-depth understanding of condensate pathology can reveal novel avenues for targeting proteinopathies linked to misfolding.

Keywords:  amyloid; biomolecular condensates; protein aggregates; protein misfolding; proteinopathies

DOI:  https://doi.org/10.3389/fmolb.2025.1719678
Cell Stress Chaperones. 2025 Dec 16. pii: S1355-8145(25)00084-7. [Epub ahead of print] 100139

Protein quality control: from molecular mechanisms to aging and disease - EMBO workshop, May 18-23, 2025, Hersonissos, Greece.

Claes Andréasson, Anat Ben-Zvi.

  Cells safeguard the functionality of the proteome using complex pathways of protein quality control. The centerpiece of this proteostasis network is a large set of molecular chaperones and proteases that impact the entire lifespan of proteins by controlling protein folding and degradation. Dysfunction of the proteostasis network is associated with many diseases and age-associated functional decline of neurons, including Alzheimer's and Parkinson's diseases, as well as several motor neuron diseases. The 2025 EMBO workshop "Protein quality control: from molecular mechanisms to aging and disease" gathered the large and interdisciplinary community of researchers that study protein quality control, from its fundamental molecular mechanisms via higher order organization in organisms to its impact on and use in the medical field. Here we summarize the workshop and report research findings.

Keywords:  Aggregation, Autophagy; Chaperone; Folding, Protein quality control; Proteostasis; Stress ubiquitin-proteasome system (UPS)

DOI:  https://doi.org/10.1016/j.cstres.2025.100139
Chembiochem. 2025 Dec 20. e202500795

Modulation of Liquid-to-Solid Phase Transition in Coacervates for Neurodegenerative Disease Treatments.

Xiaokang Wang, Minghao Wei, Yan Qiao.

  Coacervates formed through liquid-liquid phase separation represent a fundamental model for protocell and serve as a membraneless organelle in living cells, modulating various biological processes. During aging or under stress, protein misfolding and oligomerization trigger aberrant liquid-to-solid phase transition (LSPT), a process driven by multivalent interactions. These phase transitions disrupt cellular equilibrium, leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The regulatory strategies is summarize to enhance molecular interactions in coacervate LSPT into three categories, including physical stimulation, molecular modulation, and sequence regulation. This review aims to establish a conceptual framework for modulating coacervate LSPT and further explores potential clinical treatments for neurodegenerative diseases.

Keywords:  coacervate; condensate; liquid‐to‐solid phase transition; liquid–liquid phase separation; neurodegenerative diseases; protein aggregation; protocell

DOI:  https://doi.org/10.1002/cbic.202500795