bims-proned 2025-11-09 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–11–09
twenty-one papers selected by
Verena Kohler, Umeå University

Rethinking neurodegeneration through a co-proteinopathy lens.
TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?
The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.
Polyserine likes the tau and not the label.
A30P and A30G Mutations in α-Synuclein Promote Metastable Long-Lived Aggregates with Distinct Structural Responses to EGCG.
Multifractal detrended fluctuation analysis and persistent homology of α-synuclein aggregates across Parkinson's disease stages.
E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein tau.
Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.
Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking.
Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.
Deubiquitinating enzymes in parkinson's disease: molecular mechanisms and therapeutic potential.
Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies.
Pathological Folding of α-Synuclein on Polystyrene Nanoplastic Revealed by Sum Frequency Scattering and 2D Infrared Spectroscopy.
In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.
Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.
The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.
Targeting the C5-C5aR1 axis: A promising therapeutic strategy for Alzheimer's disease and amyotrophic lateral sclerosis by unlocking neuroprotection.
Chemically Fueled, Active Droplets Prevent the Aging of Peptides into Amyloid-Like Fibers.
Machine Learning-Based Bioactivity Prediction and Descriptor-Guided Rational Design of Amyloid-β Aggregation Inhibitors.
Exidavnemab binds to aggregated α-synuclein in human brains affected by α-synucleinopathies.
TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila.

Trends Neurosci. 2025 Nov 06. pii: S0166-2236(25)00219-X. [Epub ahead of print]

Rethinking neurodegeneration through a co-proteinopathy lens.

Yu P Zhang, Shekhar Kedia, David Klenerman.

  Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; coaggregation; protein aggregation; proteostasis

DOI:  https://doi.org/10.1016/j.tins.2025.10.006
Bioessays. 2025 Nov 02. e70084

TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?

Simone Mosna, Dorothee Dormann.

  TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.

Keywords:  TAR DNA binding protein of 43 kDa (TDP‐43); amyotrophic lateral sclerosis (ALS); condensates; frontotemporal dementia (FTD); kinases; neurodegeneration; phase separation; phosphorylation; protein aggregation

DOI:  https://doi.org/10.1002/bies.70084
Autophagy Rep. 2025 ;4(1): 2577406

The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.

Emily Birnbaum, Zhenyu Yue.

  Emerging evidence suggests that the propagation of α-synuclein pathology underlies the progression of Parkinson's disease and supports the hypothesis that transmission of α-synuclein aggregates contributes to dopaminergic degeneration. Autophagy, a cellular degradation process, removes protein aggregates and damaged organelles and aids in α-synuclein clearance. However, fibrillar α-synuclein aggregates may evade and even disrupt autophagy, causing toxic spread. The role of autophagy may be multifaceted in the propagation of α-synuclein: clearing α-synuclein aggregates and damaged organelles (protective) versus the release of α-synuclein aggregates (harmful). Here we review how neuronal and glial autophagy regulate α-synuclein clearance and spreading. We also discuss the need for future research to address the interplay of autophagy and α-synuclein aggregates toward therapeutic development.

Keywords:  Parkinson’s disease; autophagy; fibrils; synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1080/27694127.2025.2577406
Neuron. 2025 Nov 05. pii: S0896-6273(25)00707-X. [Epub ahead of print]113(21): 3495-3497

Polyserine likes the tau and not the label.

Jay P Ross, Aaron D Gitler.

Aggregation of the protein tau is a feature of several neurodegenerative diseases. In this issue of Neuron, Van Alstyne et al. report a polyserine-motif-based strategy to target aggregation inhibitor proteins to tau aggregates, reducing pathology and rescuing neurodegeneration in animal models.

DOI: https://doi.org/10.1016/j.neuron.2025.09.019
Biochemistry. 2025 Nov 07.

A30P and A30G Mutations in α-Synuclein Promote Metastable Long-Lived Aggregates with Distinct Structural Responses to EGCG.

Santosh Devi, Dushyant K Garg, Rajiv Bhat.

Synucleinopathies are neurodegenerative disorders marked by the accumulation of misfolded α-synuclein and its familial mutants in brain cells. The mechanistic understanding of how α-synuclein mutations exacerbate disease remains unsolved. Here, the in vitro aggregation kinetics of α-synuclein and its mutants revealed that A30P and a recently discovered A30G variant displayed aggregation kinetics uncharacteristically slower than those of wild-type (WT) and other mutants. We delineated the amyloidogenesis pathway of these variants by characterizing different intermediates through time-dependent CD and AFM analysis. AFM-Raman spectroscopy and proteinase-K digestion further distinguished structural features of these species. We infer that WT and the A30 variants aggregate through a common pathway, albeit with variant-specific rates, yielding kinetically metastable aggregates with structural differences in the order A30P < A30G < WT. These metastable aggregates underwent further rearrangements to form stable fibrils upon vigorous agitation, incubation with osmolytes, or seeding with fibrillar seeds. Addition of the amyloid-modifying compound EGCG to the metastable and the final fibrillar states converted them to β-sheet-rich small fibrillar and prefibrillar structures, respectively. However, EGCG directed monomers toward amorphous aggregation. We present a viewpoint that A30 mutations that are located outside the canonical amyloid core of α-synuclein could augment its toxic gain of function by producing kinetically long-lived prefibrillar species rather than by promoting thermodynamically alternative conformations. These kinetically metastable conformers of varying hierarchy were differentially sensitive to EGCG. Our findings provide significant insights into how α-synuclein mutations contribute to synucleinopathies and how amyloid modulators differentially act on intermediates versus mature fibrils.

DOI: https://doi.org/10.1021/acs.biochem.5c00518
J Alzheimers Dis. 2025 Nov 05. 13872877251390838

Multifractal detrended fluctuation analysis and persistent homology of α-synuclein aggregates across Parkinson's disease stages.

Pranathi Jalapally, Lakshmi Sowmya Emani, Sminu Izudheen, Jagannatha Rao K S.

  Backgroundα-Synuclein (α-syn) is a prominent protein associated with neurodegenerative conditions such as Parkinson's disease (PD), dementia, and multiple system atrophy, and is a key player in synucleinopathies. Despite its significance, the specific changes in α-syn fibril conformations during the progression of PD remain a subject of uncertainty.ObjectiveThis study investigates the structural alterations in α-syn aggregation from cerebrospinal fluid samples at different PD stages (pre-PD, mid-PD, and late-PD).MethodsIn the present study, we used multifractal detrended fluctuation analysis (MFDFA) and persistent homology. The analysis involves constructing protein contact networks for major and minor α-syn polymorphs. The subsequent application of MFDFA to vertex degree, vertex clustering coefficients, and vertex closeness centrality on this time series data reveals multifractal properties and scaling behaviors. Simultaneously, topological analyses, including Rips complexes, Alpha complexes, and Betti numbers, uncover essential structural features and connectivity patterns in α-syn networks.ResultsThis study illuminates α-syn multifractal dynamics and topological characteristics, providing valuable insights into disease-related protein aggregation and network alterations in the progression of PD.ConclusionsThis study provides unique information on MFDFA and persistent homology of α-syn aggregates across disease stages.

Keywords:  Alpha complex; Alzheimer’s disease; Betti numbers; Parkinson's disease; Rips complex; multifractal detrended fluctuation analysis; persistent homology; protein contact network

DOI:  https://doi.org/10.1177/13872877251390838
FEBS J. 2025 Nov 03.

E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein tau.

Shiho Aoki, Wataru Onodera, Akihiko Takashima, Kotaro Kawasaki, Kazuki Imadegawa, Hikaru Kurahashi, Mizuho Oishi, Toru Asahi, Yoshiyuki Soeda.

  The RING-H2 type E3 ligase Praja family is composed of E3 ubiquitin-protein ligases Praja1 and Praja2, which promote the degradation of substrates through the ubiquitin-proteasome system. Both paralogs contribute to neuronal maturation and differentiation, indicating a significant role in the nervous system. Aggregation-prone proteins associated with neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) and α-synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of the microtubule-associated protein tau (MAPT) gene, which is frequently mutated in Alzheimer's disease, is regulated by Praja2. Although the Praja family has been shown to recognize various aggregation-prone proteins as substrates, it has not been determined whether tau, a key protein that aggregates in tauopathies, is also recognized by Praja proteins. In this study, we show that Praja1, but not Praja2, recognizes tau as a candidate substrate. We observed that the tau protein level in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, the in vivo/in vitro ubiquitination assay showed that Praja1 ubiquitinates tau, indicating that it is a target substrate. Next, by combining ancestral sequence reconstruction and mutational analysis, we revealed that the Praja1-tau interaction began just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is disrupted under pathological conditions, P301L tau was introduced, resulting in a degradation similar to that of wild-type tau. These results reveal an unidentified mechanism of tau proteostasis by Praja1 and may provide insight into the pathogenesis of neurodegenerative diseases, including tauopathy.

Keywords:  E3 ubiquitin ligase; Gene duplication; Molecular evolution; Neofunctionalization; Praja family; Praja1; Substrate specificity; Tau

DOI:  https://doi.org/10.1111/febs.70303
EMBO J. 2025 Nov 03.

Annexin A7 enhances TIA1 axonal trafficking to counteract pathological aggregation in neurons.

Yu Feng, Tongshu Luan, Zhenda Zhang, Wei Wang, Yuanyuan Chu, Sijia Wan, Xiaorong Pan, Jie Li, Yifan Liu, Yaqian Xu, Kun Dou, Tong Wang.

  Directed axonal trafficking of mRNA via ribonucleoprotein (RNP) complexes is essential for neuronal function and survival. However, mechanisms governing retrograde RNP transport remain poorly understood. Here, we reveal that Annexin A7 (ANXA7) promotes the recruitment of aggregation-prone T-cell intracellular antigen 1 (TIA1)-containing RNPs to cytoplasmic dynein, enabling their retrograde trafficking to the soma for degradation. Both persistent and transient Ca²⁺ elevation disrupted this function of ANXA7, leading to the detachment of TIA1 granules from dynein, impairing their transport, and subsequently triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, preventing their transport and inducing pathological aggregation of TIA1, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression reinforces trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. We describe here a Ca2+ -regulated mechanism which modulates retrograde axonal trafficking of RNPs and prevents the formation of pathological aggregates in axons.

Keywords:  Axon Trafficking; Calcium Signaling; Dynein; Phase Separation; Protein Aggregates

DOI:  https://doi.org/10.1038/s44318-025-00609-8
Mol Syst Biol. 2025 Nov 05.

Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking.

Michaela Brezinova, Z Faidon Brotzakis, Robert I Horne, Vaidehi Roy Chowdhury, Rebecca C Gregory, Yuqi Bian, Alicia González Díaz, Francesco Gentile, Michele Vendruscolo.

  Alzheimer's disease is characterized by the aggregation of the Aβ peptide into amyloid fibrils. According to the amyloid hypothesis, pharmacologically targeting Aβ aggregation could result in disease-modifying treatments. The identification of inhibitors of Aβ aggregation, however, is complicated by complex technical challenges, which typically restrict to tens of thousands the number of compounds that can be screened in experimental aggregation assays. Here, we report a computational route to increase by 4 orders of magnitude the number of screenable compounds. We achieve this result by developing an open source pipeline version of the Deep Docking protocol, and illustrate its application to the discovery of secondary nucleation inhibitors of Aβ aggregation from an ultra-large chemical library of over 539 million compounds. The pipeline was used to prioritize 35 candidate compounds for in vitro testing in Aβ aggregation assays. We found that 19 of these compounds inhibit Aβ aggregation (54% hit rate). The two most potent compounds showed potency better than adapalene, a previously reported potent inhibitor of Aβ aggregation. Consistent with the intended mechanism of action, these two compounds also proved to be high-affinity binders of Aβ fibrils with an equilibrium dissociation constant in the low nanomolar range in surface plasmon resonance experiments. These results provide evidence that structure-based docking methods based on deep learning represent a cost-effective and rapid strategy to identify potent hits for drug development targeting protein misfolding diseases.

Keywords:  Alzheimer’s Disease; Aβ42 Aggregation; Molecular Docking; Secondary Nucleation; Virtual Screening

DOI:  https://doi.org/10.1038/s44320-025-00159-5
Chem Biol Drug Des. 2025 Nov;106(5): e70189

Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.

Shahrazad Polk, Mana Rassaeikashuk, Ramasamy Thilagavathi, Chelliah Selvam.

  Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.

Keywords:  Alzheimer diseases; DNA repair; PARP1; PARylation; Parkinson disease; aging

DOI:  https://doi.org/10.1111/cbdd.70189
Mol Med. 2025 Nov 07. 31(1): 329

Deubiquitinating enzymes in parkinson's disease: molecular mechanisms and therapeutic potential.

Yarong Wu, Yu Deng, Qi Ai, Yingzhou Li, Feiya Qin, Muzaffar Hammad, Ziyao Meng, Xiaoxia Xu, Jurui Wei, Houming Yu, Guang Liang, Xia Zhao.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of α-synuclein aggregates and the selective degeneration of dopaminergic neurons in the substantia nigra. Growing evidence implicates dysfunction of the ubiquitin-proteasome system (UPS), a critical regulator of protein homeostasis, in the pathogenesis of PD through impaired clearance of toxic protein species. As key components of the UPS, deubiquitinating enzymes (DUBs) counterbalance ubiquitin ligase activity by cleaving ubiquitin chains from substrate proteins, thereby playing pivotal roles in maintaining protein turnover and regulating cellular signaling pathways. Notably, emerging research has demonstrated that specific DUBs are intimately involved in modulating multiple PD-related pathological processes, including α-synuclein aggregation, mitochondrial oxidative stress, iron homeostasis, and neuronal survival. These findings suggest DUBs as promising therapeutic targets for PD intervention. This review comprehensively summarize the pathophysiological roles of PD-associated DUBs, their molecular mechanisms in disease progression, and recent advances in the development of DUB inhibitors as potential disease-modifying therapies for PD.

Keywords:  Deubiquitinating enzymes; Inhibitors of dubs; Parkinson's disease; Physiological function, therapeutic implications

DOI:  https://doi.org/10.1186/s10020-025-01389-x
Mol Neurodegener. 2025 Nov 03. 20(1): 117

Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies.

Hiroaki Sekiya, Tomoyasu Matsubara, Michael A DeTure, Dennis W Dickson.

  Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer's disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson's disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer's disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.

Keywords:  Alpha-synuclein; Comorbid pathology; Dementia with Lewy bodies; Lewy bodies; Lewy body dementia; Machine learning algorithms; Neuropathology; Oligomers; Parkinson’s disease dementia; Prion-like propagation

DOI:  https://doi.org/10.1186/s13024-025-00900-6
J Phys Chem Lett. 2025 Nov 06. 11893-11900

Pathological Folding of α-Synuclein on Polystyrene Nanoplastic Revealed by Sum Frequency Scattering and 2D Infrared Spectroscopy.

Akriti Mishra, Thaddeus W Golbek, Asger Berg Thomassen, Lorena Zuzic, Lars Schmüser, Khezar Hayat Saeed, Fani Madzharova, Janni Nielsen, Birgit Schiøtt, Daniel E Otzen, Tobias Weidner.

The impact of micro- and nanoplastics (MNPs) on human health is a growing field of research. Reports that MNPs can breach the blood-brain barrier and accumulate inside the brain have raised concerns over their possible involvement in the development of neurogenerative diseases. The aggregation of the abundant neuronal protein α-synuclein (α-syn) is pertinent to almost 50 neurological diseases including Parkinson's disease (PD). The role of nanoplastics in the formation of toxic aggregates is unclear and has been shown to depend strongly on the type of plastics. Here we report the molecular structure and orientation of human α-syn adsorbed on polystyrene NPs using interface-specific sum frequency scattering (SFS) and structure-sensitive two-dimensional infrared (2D IR) spectroscopy. The SFS experimental data were compared with the calculated spectra of several thousands of α-syn conformations generated from molecular dynamics simulations. The SFS results reveal that α-syn folds on polystyrene nanoplastics, adopting a partly helical structure with the N-terminus and nonamyloid component regions directly bound on the polystyrene nanosurface, while the C terminus protrudes away from the polystyrene interface. 2D IR results suggest that the entire α-syn corona comprises of partly aggregated α-syn structures, built of an ordered core enclosed with flexible dynamic regions. The data shed light on the mechanism by which α-syn folds and forms aggregates at the plastic particle surfaces, a link that has been missing in understanding the role of nanoplastic in the pathogenesis of PD and related neurodegenerative diseases.

DOI: https://doi.org/10.1021/acs.jpclett.5c02526
Biochem Biophys Res Commun. 2025 Nov 02. pii: S0006-291X(25)01615-8. [Epub ahead of print]790 152899

In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.

Sahar Samsami, Mohammad Daroon Parvar, Havva Mehralitabar, Najme Dehghanbanadaki, Hossein Naderi-Manesh.

  Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.

Keywords:  Aggregation; Alzheimer's disease; Amyloid peptide; Aβ42; CNS-11

DOI:  https://doi.org/10.1016/j.bbrc.2025.152899
Neurochem Int. 2025 Oct 30. pii: S0197-0186(25)00155-X. [Epub ahead of print]191 106082

Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.

Kanako Fujii, Toshihide Takeuchi, Yuzo Fujino, Noriko Tanaka, Nao Fujino, Akiko Takeda, Eiko N Minakawa, Yoshitaka Nagai.

  Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an AppNL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated AppNL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

Keywords:  Aggregation; Alzheimer's disease; Amyloid β; Arginine; Chemical chaperone; Disease-modifying therapy; Repositioning

DOI:  https://doi.org/10.1016/j.neuint.2025.106082
Front Pharmacol. 2025 ;16 1693805

The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.

Hassan H Alhassan, Komal Janiyani, Malvi Surti, Mohd Adnan, Mitesh Patel.

  Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.

Keywords:  autophagy; cellular homeostasis; glycogen synthase kinase-3 beta; neurodegenerative diseases; protein aggregation

DOI:  https://doi.org/10.3389/fphar.2025.1693805
Biochem Pharmacol. 2025 Nov 02. pii: S0006-2952(25)00783-X. [Epub ahead of print]243(Pt 1): 117518

Targeting the C5-C5aR1 axis: A promising therapeutic strategy for Alzheimer's disease and amyotrophic lateral sclerosis by unlocking neuroprotection.

Tong-Qi Ge, Pu Wang, Pei-Pei Guan.

  C5aR1 is a G protein-coupled receptor (GPCR) which is involved in exacerbating neurodegenerative diseases, including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). This review highlights the critical role of the C5-C5aR1 axis, in the pathogenesis of neurodegenerative diseases such as AD and ALS. In AD and ALS, abnormal protein aggregates activate the complement system (CS), leading to increased production of C5a. C5a activates C5aR1 on microglia, triggering the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that induce synaptic loss. Concurrently, the C5-C5aR1 axis impairs microglial phagocytic capacity, promoting damage-associated molecular patterns (DAMPs) accumulation and forming a vicious cycle of inflammation and complement activation. Additionally, excessive complement molecule assembles into the terminal complement complex (TCC), which exerts direct neurotoxic effects and drives neuronal apoptosis. Preclinical studies show that C5aR1 antagonists, such as PMX205, mitigate disease progression in AD and ALS animal models by reducing neuroinflammation and preserving synaptic function. These findings underscore the C5-C5aR1 axis as a promising target for neurodegenerative disease therapy and highlight the need for further development of potential antagonists of C5aR1.

Keywords:  C5; C5aR1; GPCR signaling; Neurodegenerative disease; Therapy

DOI:  https://doi.org/10.1016/j.bcp.2025.117518
J Am Chem Soc. 2025 Nov 06.

Chemically Fueled, Active Droplets Prevent the Aging of Peptides into Amyloid-Like Fibers.

Monika Wenisch, Michele Stasi, Simone M Poprawa, Brigitte A K Kriebisch, Job Boekhoven.

Protein aggregation is a hallmark of molecular aging and is implicated in various neurodegenerative diseases. Aggregation proceeds via autocatalytic, thermodynamically favored pathways. Yet in living systems, dynamic, active regulation and compartmentalization─such as in biomolecular condensates─can suppress or delay such irreversible assembly. Here, we describe a peptide that exhibits pathway-dependent self-assembly into either amyloid-like fibers or fuel-driven droplets. The peptide was designed to undergo chemical activation via a carbodiimide-driven reaction cycle, which transiently neutralizes its overall charge and promotes droplet formation. In the absence of fuel, the peptide slowly self-assembles into stable fibers through an autocatalytic process resembling amyloid aging. However, upon repeated or continuous fueling, the peptide forms active droplets that persist for days and remain resistant to fiber formation. Thus, we demonstrate that the fuel-driven active state can completely suppress fiber nucleation and growth. These findings demonstrate that the constant turnover of peptides through activation and deactivation can act as a kinetic sink, sequestering peptides and delaying the transition to the thermodynamically favored fiber state. Our results establish a minimal, chemically controlled system in which phase behavior and aging can be modulated by energy input. This work provides new insight into how nonequilibrium processes can temporally regulate self-assembly, mimicking cellular strategies for protein homeostasis. More broadly, it offers a model for studying the prevention of pathological aggregation and opens routes toward designing synthetic systems that emulate the dynamic regulation of living matter.

DOI: https://doi.org/10.1021/jacs.5c12831
ACS Chem Neurosci. 2025 Nov 05.

Machine Learning-Based Bioactivity Prediction and Descriptor-Guided Rational Design of Amyloid-β Aggregation Inhibitors.

Avantika Bansal, Akshat Raj Sharma, Arya Chakraborty, Aditya Sunkaria, Alok Jain.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid-β (Aβ) aggregation plays a pivotal role in its onset and progression. Inhibiting Aβ aggregation is a promising therapeutic strategy; however, its intrinsically disordered and conformationally flexible nature hinders both conventional and computational inhibitor design. Moreover, experimental development of Aβ inhibitors, encompassing molecular design, synthesis, and biological evaluation through repeated assays, is a slow, labor-intensive, and resource-intensive process. Therefore, robust design guidelines and predictive tools are essential for accelerating the discovery of Aβ inhibitors. To overcome these limitations, we developed a machine-learning-based, user-friendly web platform, Amylo-IC50Pred (https://amyloic50pred.vercel.app/), for rapid virtual screening of small molecules targeting Aβ aggregation. The platform integrates two classification models and one regression model, trained on 584 biologically validated compounds. For inhibitor-decoy discrimination, the Random Forest algorithm achieved perfect accuracy (100%). Potency classification into potent, moderately potent, and poor inhibitors was best achieved using Histogram-based Gradient Boosting (81% accuracy). The IC50 regression model, also based on Random Forest, achieved a coefficient of determination (R2) of 0.93, demonstrating strong predictive performance. 2D and 3D key molecular properties such as hydrophobicity, shape and charge distribution, and molecular symmetry were identified as critical contributors to model performance. Importantly, these identified properties provide valuable insights into the molecular features that govern Aβ aggregation inhibition and can serve as a foundation for rational design of potent and selective Aβ aggregation inhibitors. Amylo-IC50Pred thus represents a valuable resource for accelerating AD drug discovery.

Keywords:  Alzheimer’s; Aβ aggregation; IC50; machine learning; molecular descriptors

DOI:  https://doi.org/10.1021/acschemneuro.5c00649
Neurotherapeutics. 2025 Nov 05. pii: S1878-7479(25)00257-0. [Epub ahead of print] e00779

Exidavnemab binds to aggregated α-synuclein in human brains affected by α-synucleinopathies.

Olof Zachrisson, Malin Johannesson, Linda Söderberg, Fredrik Eriksson, Dan Sunnemark, Eva Nordström, My Björklund, Emily B Button, Tomas Odergren, Christer Möller, Gunilla Osswald, Johanna Fälting.

  Abnormal accumulation of α-synuclein in neuronal and/or glial cells occurs in a range of neurodegenerative conditions, including Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunotherapy targeting α-synuclein is a rational treatment strategy for these α-synucleinopathies. Exidavnemab (also known as BAN0805 or ABBV-0805) is a monoclonal antibody with a high affinity and selectivity for pathological aggregated forms of α-synuclein, and a low affinity for physiological monomers. Exidavnemab is presently in clinical development as a disease-modifying treatment for patients with α-synucleinopathy. To provide information relevant to human target engagement, the present study investigated exidavnemab binding ex vivo using human post mortem brain tissues. Immunohistochemistry experiments demonstrated that exidavnemab bound to aggregated α-synuclein in tissues from individuals affected by Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunoprecipitation using exidavnemab effectively removed α-synuclein aggregates from Triton-soluble brain tissue extracts. Data from these ex vivo studies using human tissues are consistent with clinical findings and provide further support for the continued development of exidavnemab as a potential treatment for multiple forms of α-synucleinopathy.

Keywords:  ABBV-0805; BAN0805; Exidavnemab; Immunotherapy; Neuronal α-synuclein disease

DOI:  https://doi.org/10.1016/j.neurot.2025.e00779
Front Cell Dev Biol. 2025 ;13 1677090

TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila.

Davide Colaianni, Nadia Ceccato, Pietro Antolini, Carmela Conte, Cristiano De Pittà, Fabian Feiguin, Gabriella M Mazzotta.

  Transactive response DNA-binding protein 43 (TDP-43) is a key factor in motor neurons and related neurodegenerative disorders, and the presence of cytoplasmic aggregates of TDP-43 is a major hallmark of diseases such amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nevertheless, little is known about early developmental effects or the systemic nature of TDP-43-mediated pathology. Drosophila melanogaster is acknowledged as a powerful genetic model for studying the genetic inheritance and the behavioral and developmental processes associated with human neurodegenerative diseases, including ALS. To better understand the possible roles and potential pathogenic mechanisms of TDP-43 protein in the pathogenesis of ALS, we performed a transcriptomic analysis of larvae from a Drosophila model knock-out (KO) for the TBPH gene, the fly TDP-43 ortholog. Interestingly, the Gene Ontology (GO) analysis highlighted some pathways not yet associated with this pathology and this model. We identified several genes encoding for serine proteases, a class of enzymes that in the central nervous system (CNS) play important roles in neural development, synaptic plasticity, and neurodegeneration. Our work provides insights into novel pathological mechanisms underlying the disease, thereby opening new pathways for drug discovery.

Keywords:  Drosophila melanogaster; TBPH; TDP-43; amyotrophic lateral sclerosis; gene expression

DOI:  https://doi.org/10.3389/fcell.2025.1677090