bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–11–02
seventeen papers selected by
Verena Kohler, Umeå University
  1. Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.
  2. Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.
  3. α-Synuclein Early-Oligomers Regulate Self-Assembly through Nucleation and Liquid-Liquid Phase Separation.
  4. Baicalein inhibits amyloid beta42 aggregation through disruption of the Asp23-Lys28 salt bridge.
  5. DDOX expands the repertoire of tetracyclines for Parkinson's disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils.
  6. MPP+ induces α-synuclein oligomerization and neurite impairment by disrupting mitochondrial function and Akt signaling, with apigenin emerging as a potential neuroprotective agent.
  7. Analysis of Single Particles of Amyloid Beta and α-Synuclein With Seeded Amplification for the Diagnosis of Alzheimer's and Parkinson's Disease.
  8. A high-throughput drug screening assay for anti-tau aggregation using split GFP and flow cytometry.
  9. A Conserved MicroRNAs Motif Reveals TDP-43 Pathology and MAPK Pathway Activation in Parkinson's Disease.
  10. A Mathematical Model of Cellular Aggregation Predicts Patterns of Tau Accumulation in Neurodegenerative Disease.
  11. FibrilPaint to determine the length of Tau amyloids in fluids.
  12. Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.
  13. Repulsive vs Attractive Crowding Distinctly Regulate TDP-43 Condensates through Region-specific Structural Dynamics.
  14. Aggregation Characteristics of Tau Phosphorylated by Various Kinases as Observed by Quantum Dot Fluorescence Imaging.
  15. Aggregation and Propagation of α-Synuclein in Parkinson's Disease: A Bibliometric Perspective.
  16. Unveiling the phenylalanine coaggregation mechanism for a deep understanding of phenylketonuria disease.
  17. Aloe Vera Inhibits Protein Fibrillation: Mechanistic Biophysical Evaluation.
  1. Life Sci. 2025 Oct 26. pii: S0024-3205(25)00691-5. [Epub ahead of print]382 124055
    Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.
    Tejas Bhatia, Angel Godad.
      Neurodegenerative diseases (NDDs), including Alzheimer's Disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal dysfunction and protein aggregation. There is a growing body of evidence suggesting that the collapse of proteostasis, the failure of protein homeostasis, is an important contributor to neurotoxicity. In this review, we suggest that this collapse is exacerbated by ionic dysregulation, an important but under-addressed cause of neurodegeneration. Importantly, breakdowns in chloride, bicarbonate, sodium, and calcium homeostasis alter fundamental aspects of cellular physiology, including important aspects of TDP-43 phase separation and tau hyperphosphorylation and aggregation. We suggest that the relationship of proteostasis failure and ionic dysregulation is a bidirectional feedback loop that accelerates the progression of neurodegeneration. Some therapeutic strategies aimed at correcting these mechanisms-including small-molecule chaperone inducers, autophagy inducers, and ion-channel modulators-might hold the potential for disease modification. In this review, we document the complex intersections of proteostasis failure and ionic dysregulation in TDP-43 and tauopathies and provide new ideas for therapies and future studies.
    Keywords:  Autophagy; Bicarbonate; Chloride; Ionic dysregulation; Neurodegeneration; Phase separation; Proteostasis; TDP-43; Tau
    DOI:  https://doi.org/10.1016/j.lfs.2025.124055
  2. Mol Neurodegener. 2025 Oct 27. 20(1): 113
    Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.
    Yongzhen Miao, Ting Zhang, Zhuoya Ma, Huanhuan Du, Qipei Gu, Mengni Jiang, Kangping Xiong, Chun-Feng Liu, Hongrui Meng.
       BACKGROUND: The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.
    METHODS: To this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.
    RESULTS: We found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.
    CONCLUSIONS: These findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.
    Keywords:  Neuroinflammation; O-GlcNAcylation; Proteolysis; α-synuclein
    DOI:  https://doi.org/10.1186/s13024-025-00904-2
  3. Biomacromolecules. 2025 Oct 28.
    α-Synuclein Early-Oligomers Regulate Self-Assembly through Nucleation and Liquid-Liquid Phase Separation.
    Mengrui Wei, Wanlu Han, Fei Xu, Shuo Yang, Wenjing Liu, Xinrui Gui, Ziwei Chang, Jun Yang, Zheng Niu.
      The aggregation and deposition of α-synuclein (α-syn) in Lewy bodies is the prominent pathological hallmark of Parkinson's disease. α-Syn aggregation proceeds via liquid-liquid phase separation (LLPS) and liquid-to-solid phase transition (LSPT) within the dense phase, leading to fibril formation. In this study, we reconstituted an instantaneous LLPS system for α-syn, which is primarily governed by electrostatic interactions, uncovering the structure of early-stage oligomers within the dense phase. LLPS promoted the α-syn aggregation process via its intricate nucleation and oligomerization steps, yielding liquid-like droplets composed of hollow spherical oligomers with a loosely packed β-turn conformation. The solidification of dynamic condensates via LSPT, leading to amyloid deposition, may serve as an underlying mechanism for α-syn aberrant aggregation. Our findings deepen the understanding of α-syn self-assembly within the dense phase and provide critical insights into the molecular mechanisms underpinning aggregation kinetics, holding promise for future therapeutic strategies.
    DOI:  https://doi.org/10.1021/acs.biomac.5c01543
  4. Sci Rep. 2025 Oct 31. 15(1): 38237
    Baicalein inhibits amyloid beta42 aggregation through disruption of the Asp23-Lys28 salt bridge.
    Faisal Nabi, Owais Ahmad, Mohammad Rehan Ajmal, Mohd Amir, Iram Parveen, Fahad M Almutairi, Rizwan Hasan Khan.
      The aggregation of amyloid beta-42 (Aβ42) into β-sheet-rich fibrillar structures is a critical pathogenic feature of Alzheimer's disease (AD). Baicalein (BCN), a natural flavonoid, has been shown to inhibit aggregation in amyloidogenic proteins, including human islet amyloid polypeptide (hIAPP), which shares structural similarities with Aβ42. This study investigates the inhibitory and disaggregation effects of BCN on Aβ42 using biophysical assays and atomistic molecular dynamics (AT-MD) simulations. Thioflavin-T (ThT) fluorescence, circular dichroism (CD) spectroscopy, and fluorescence microscopy reveal that BCN significantly reduces fibril formation and induces disaggregation of preformed Aβ42 fibrils in a concentration-dependent manner. Dynamic light scattering (DLS) analysis further confirms that BCN stabilizes Aβ42 in its monomeric form, preventing the formation of larger aggregates. AT-MD simulations show that BCN interacts with the aggregation-prone region of Aβ42, specifically disrupting the Asp23-Lys28 salt bridge, which is crucial for β-sheet formation. The simulations also reveal that BCN promotes the formation of α-helical structures, reducing β-sheet content and hindering aggregation. Secondary structure analysis via DSSP plots confirms that BCN shifts Aβ42 towards less aggregation-prone conformational states. These results highlight BCN's dual function in inhibiting both the formation and disaggregation of Aβ42 fibrils. This study provides mechanistic insights into BCN's therapeutic potential for amyloid-related diseases, suggesting that it can effectively target the β-sheet spine structures common to multiple amyloidogenic proteins, offering a promising approach for mitigating AD progression.
    Keywords:  Alzheimer’s disease; Amyloid beta42; Baicalein; Molecular simulations; Protein aggregation
    DOI:  https://doi.org/10.1038/s41598-025-21991-7
  5. Sci Rep. 2025 Oct 29. 15(1): 37769
    DDOX expands the repertoire of tetracyclines for Parkinson's disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils.
    María Del Milagro Teran, Rodrigo Hernán Tomas-Grau, Estefanía Silvana Soliz-Santander, María Laura Guayán, Valentina Budeguer Isa, Alvaro Luna Mercado, Cesar Luis Avila, Bernardo Sosa-Padilla, Hernán Cruz, Ismaila Ciss, Pierre Besnault, Sergio Benjamín Socias, Esteban Vera Pingitore, Laurent Ferrié, Rita Raisman-Vozari, Patrick Pierre Michel, Bruno Figadère, Rosana Nieves Chehín, Diego Ploper.
      The increasing prevalence of Parkinson's disease (PD) requires innovative multi-targeted disease-modifying therapies to counteract the toxicity associated with the amplification, propagation, and accumulation of alpha-synuclein (α-Syn) aggregates in the brain. Tetracyclines, particularly doxycycline, have demonstrated multimodal neuroprotective effects, both in vitro and in vivo. The non-antibiotic derivative of doxycycline 4-dedimethylamino-12a-deoxydoxycycline (DDOX), has been recently shown to rescue neurons from oxidative injury. Here, we demonstrate that DDOX showcases a diverse range of mechanisms targeting α-Syn aggregates. Notably, DDOX inhibited the aggregation of α-Syn and the seeding ability of α-Syn pre-formed fibrils (PFF) in biophysical and cellular assays. In addition, the compound ameliorated the relocalization of total and phospho-α-Syn, triggered by exogenous α-Syn PFF. Surprisingly, DDOX drastically mitigated lysosomal stress induced by these aggregates. Moreover, we determined that DDOX effectively impeded the internalization of fluorescently labeled α-Syn PFF. Biophysical techniques and molecular docking simulations suggest that DDOX binds to hydrophobic patches on α-Syn fibrils. Our findings reveal novel neuroprotective attributes of tetracyclines, wherein a direct extracellular interaction between DDOX and α-Syn aggregated species mitigates their intracellular impact. These results provide a promising foundation for DDOX, a drug that aims to interfere with the intracellular seeding, propagation and uptake of α-Syn fibrils in neurodegenerative conditions.
    Keywords:  Alpha-synuclein; Doxycycline; PFF; Parkinson’s disease; Preformed fibril; Tetracyclines; Uptake
    DOI:  https://doi.org/10.1038/s41598-025-15991-w
  6. Food Chem Toxicol. 2025 Oct 27. pii: S0278-6915(25)00589-7. [Epub ahead of print] 115821
    MPP+ induces α-synuclein oligomerization and neurite impairment by disrupting mitochondrial function and Akt signaling, with apigenin emerging as a potential neuroprotective agent.
    Ratchaneekorn Reudhabibadh, Nidanut Champoochana, Zulkiflee Kuedo, Peungchaleoy Thammanichanon, Pilaiwanwadee Hutamekalin, Thunwa Binlateh.
      Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by α-synuclein accumulation and mitochondrial impairment. Mitigating α-synuclein aggregation and mitochondrial dysfunction are prominent strategies in PD treatment. Apigenin, a dietary flavonoid, exhibits anti-inflammatory neuroprotective potential in PD models. However, it is still unclear whether apigenin possesses any impact on α-synuclein aggregation and mitochondrial dysfunction. Here, the effects and underlying mechanism of apigenin were investigated using MPP+-induced PD-like pathology in SH-SY5Y cells. Our results showed that apigenin significantly ameliorated neuronal apoptosis through inhibiting Bax/caspase-3 pathway and activating Bcl-2, increased size of SH-SY5Y neurospheres, and attenuated the levels of α-synuclein oligomers in MPP+-treated cells. Furthermore, apigenin improved MPP+-induced neurite damage as indicated by increased neurite length and expression of tyrosine hydroxylase (TH), growth associated protein 43 (GAP-43) and post-synaptic density protein (PSD-95). Increased ROS levels, depleted ATP levels, and decreased mitochondrial membrane potential and p-Drp1 expression in MPP+-treated cells were alleviated by apigenin. Further studies revealed that apigenin could enhance Akt activity. By using a specific Akt inhibitor, perifosine, the effects of apigenin on preventing MPP+-triggered PD pathologies were eliminated. Together, this work demonstrated that apigenin exerted neuroprotection by mitigating α-synuclein oligomers, neurite damage, mitochondrial dysfunction and neuronal apoptosis via Akt-dependent mechanism.
    Keywords:  Akt; Drp1; mitochondrial dysfunction; neurite damage; α-synuclein oligomer
    DOI:  https://doi.org/10.1016/j.fct.2025.115821
  7. Biotechnol Appl Biochem. 2025 Oct 31.
    Analysis of Single Particles of Amyloid Beta and α-Synuclein With Seeded Amplification for the Diagnosis of Alzheimer's and Parkinson's Disease.
    Alexandra Dybala, Marlene Pils, Oliver Bannach, Gültekin Tamgüney, Detlev Riesner.
      Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the pathological aggregation of specific proteins such as amyloid beta (Aβ) and α-synuclein, respectively. Early detection of these protein aggregates in biological fluids could facilitate timely diagnosis and therapeutic intervention. This study explores an aggregate amplification approach using the surface-based fluorescence intensity distribution analysis (sFIDA) method to enhance the detection sensitivity of Aβ and α-synuclein seeds. Two amplification strategies were investigated: surface-bound and solution-phase amplification. In the case of Aβ, surface-bound amplification using immobilized Aβ-specific antibodies was tested with synthetic Aβ1-42 seeds and monomeric Aβ1-42 as the substrate. Despite observable aggregation, self-aggregation of the monomeric substrate interfered with seed-dependent amplification, rendering the approach ineffective at physiologically relevant concentrations. Attempts to suppress self-aggregation using blocking peptides, bovine serum albumin, and truncated Aβ11-42 substrates were unsuccessful. Solution-phase amplification followed by surface detection also failed to reliably differentiate seeded aggregation from self-aggregation, indicating that Aβ amplification is unsuitable for diagnostic applications. In contrast, α-synuclein exhibited significantly lower self-aggregation, allowing for more effective seeded amplification. Surface-bound α-synuclein amplification successfully detected synthetic seeds at nanomolar concentrations, while solution-phase amplification further improved sensitivity, enabling detection down to the picomolar range. The method was successfully applied to brain homogenates from transgenic PD model mice, demonstrating the potential for detecting α-synuclein seeds in biological samples. These findings highlight the limitations of Aβ amplification for diagnostic purposes while supporting the feasibility of α-synuclein amplification for PD detection. Future work will focus on optimizing this approach for clinical applications.
    Keywords:  aggregation; biomarker; neurodegenerative diseases; pathology; seeds; surface‐based fluorescence intensity distribution analysis (sFIDA)
    DOI:  https://doi.org/10.1002/bab.70083
  8. Sci Rep. 2025 Oct 29. 15(1): 37866
    A high-throughput drug screening assay for anti-tau aggregation using split GFP and flow cytometry.
    Omnia M H Ibrahium, Taiwo A Ademoye, Jessica S Fortin, Raluca Ostafe.
      Tau protein aggregation is a hallmark of neurodegenerative diseases, including Alzheimer's disease, making the development of anti-aggregation therapeutics a critical area of research. Progress in drug discovery has been hindered by the lack of efficient screening methods that accurately reflect cellular conditions. We present a high-throughput cell-based assay utilizing split GFP technology to monitor tau aggregation in living cells. Our system employs suspension-adapted HEK293 cells co-transfected with tau proteins fused to complementary GFP fragments, producing fluorescent signals upon tau aggregation. Notably, our system demonstrates tau aggregation without external aggregation inducers, likely due to the enhanced protein expression in suspension-adapted cells. Validation with a known urea-based tau aggregation inhibitor showed dose-dependent reduction in fluorescence, corresponding to decreased tau aggregation. The assay's flow cytometry compatibility enables rapid, quantitative analysis of large sample sets while allowing simultaneous assessment of compound efficacy and cytotoxicity. This method advances tau aggregation monitoring and drug discovery by providing a physiologically relevant platform for identifying novel anti-tau aggregation therapeutics.
    DOI:  https://doi.org/10.1038/s41598-025-21680-5
  9. FASEB J. 2025 Nov 15. 39(21): e71186
    A Conserved MicroRNAs Motif Reveals TDP-43 Pathology and MAPK Pathway Activation in Parkinson's Disease.
    Mingyue Luan, Wei Wu, Fuze Zheng, Yunchuang Sun, Luhua Wei, Fan Li, Kai Li, Jing Chen, Wei Sun, Li Zhu, Zhaoxia Wang, Jianwen Deng.
      Parkinson's disease (PD), the second most common neurodegenerative disorder, involves dopaminergic neuron loss and α-synuclein (α-syn) aggregation. Recent studies have shown that dysregulation of microRNAs (miRNAs) is associated with PD, but little is known about its pathological mechanism. Here, we identified a conserved 5-nucleotide motif (HBCCC; H = U, A, or C; B = U, C, or G) in 52 downregulated miRNAs from the salivary RT-QuIC (real-time quaking-induced conversion)-positive PD patients, accounting for 82.5% of these dysregulated miRNAs. The motif-containing miRNAs, including miRNA-6812-3p and miRNA-6848-3p, were also significantly downregulated in the substantia nigra of PD patients. Quantitative Real-Time PCR (RT-qPCR), miRNA pull-down assay, and western blot confirmed that TAR DNA binding protein-43 (TDP-43) bound to the motif-containing miRNAs in vitro and was responsible for the biogenesis of these miRNAs. Furthermore, we found that TDP-43 co-aggregated with α-syn in vitro and in vivo, which could be responsible for the downregulation of miRNAs. Motif-containing miRNAs targeted the mitogen-activated protein kinase (MAPK) pathway, and their downregulation in PD activated this pathway, as revealed by bioinformatic analysis. Interfering with MAPK expression alleviated movement disorders in a Drosophila PD model. These findings provide a potential therapeutic target for PD and highlight the pathological role of miRNAs in neurodegenerative diseases.
    Keywords:  MAPK; PD; TDP‐43; microRNA; motif
    DOI:  https://doi.org/10.1096/fj.202502382RR
  10. Adv Sci (Weinh). 2025 Oct 27. e11297
    A Mathematical Model of Cellular Aggregation Predicts Patterns of Tau Accumulation in Neurodegenerative Disease.
    Shih-Huan Huang, Annelies Quaegebeur, Tanrada Pansuwan, Timothy Rittman, Ruiyan Wang, Tuomas Pj Knowles, James B Rowe, David Klenerman, Georg Meisl.
      Protein aggregates are a hallmark of neurodegenerative disease, yet the molecular processes that control their appearance remain incompletely characterized. In particular, it is unknown to what degree the development of aggregates in one cell is triggered by nearby aggregate-containing cells, as opposed to proceeding cell-autonomously. Here, a minimal, bottom-up computational model is developed that is characterized by just two parameters: the relative rate of cell autonomous and cell-to-cell triggers of aggregation and a length scale of cell-to-cell interactions. Its applicability is demonstrated in the primary tauopathy Progressive Supranuclear Palsy by extracting mechanistic information from the distribution of tau aggregates at different disease stages from post-mortem human brain. Despite its simplicity, the model is able to reproduce the aggregate patterns observed in the data and reveals that the triggering of aggregation by nearby aggregated cells, over distances of ≈100 µm, is the major driver of disease progression once a low threshold level of aggregates is reached. The model also provides a natural explanation for an increase in the rate of disease progression when this threshold is reached, providing fundamental new insights into disease mechanisms and predicting the efficiency of different therapeutic strategies.
    Keywords:  mechanistic model; molecular mechanism; neurodegeneration; protein aggregation; tauopathy
    DOI:  https://doi.org/10.1002/advs.202511297
  11. Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2502847122
    FibrilPaint to determine the length of Tau amyloids in fluids.
    Júlia Aragonès Pedrola, Françoise A Dekker, Tommaso Garfagnini, Guy Mayer, Margreet B Koopman, Menno Bergmeijer, Gobert Heesink, Iris Rots, Mireille M A E Claessens, Friedrich Förster, Jeroen J M Hoozemans, Henrik Jensen, Assaf Friedler, Stefan G D Rüdiger.
      Tau aggregation into amyloid fibrils is linked to the development of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular processes driving aggregation in disease are still being uncovered, highlighting the need for innovative tools to study aggregation reactions. Here, we introduce FibrilPaint1 as a tool to measure the size of Tau amyloid fibrils in fluids, from early aggregation stages to mature fibrils. FibrilPaint1 is a 22mer peptide with exciting properties: i) FibrilPaint1 binds fibrils with nanomolar affinity; ii) it also binds to precursors, down to a size of only 4 layers; iii) it does not bind to monomers; iv) it is fluorescently labeled, which allows monitoring and localizing interactions; v) FibrilPaint1 recognizes various Tau fibrils, including patient-derived fibrils from AD, corticobasal degeneration (CBD), and frontotemporal dementia (FTD); vi) it also binds to fibrils from amyloids derived from Amyloid-β, α-synuclein, and huntingtin vii) FibrilPaint1 is selective for the amyloid state and does not have background binding to amorphous aggregates, blood serum, or cell lysate. In combination with flow-induced dispersion analysis (FIDA), a microfluidics technology, we determined the molecular size of amyloid fibrils with submicroliter sample volumes. This setup acts as a molecular ruler at layer resolution-we determined Tau fibril length from 4 to 1100 layers in solution. This is an interesting parameter for molecular studies in dementia, with potential for diagnostic applications.
    Keywords:  Tau; microfluidics; protein aggregation
    DOI:  https://doi.org/10.1073/pnas.2502847122
  12. Front Aging Neurosci. 2025 ;17 1688554
    Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.
    Feng Tao, Mengxuan Lin, Xiang Meng, Linghui Huang, Bifang Zhuo, Siyi Jiang, Shizhe Deng, Zhihong Meng, Jiangwei Shi.
      Copper (Cu) is a vital trace element required for sustaining life and is involved in numerous critical metabolic processes within the body. Cuproptosis, a newly recognized type of Cu-dependent cell death, is mechanistically distinct from apoptosis, autophagy, pyroptosis, and ferroptosis. It is characterized by abnormal Cu accumulation and aberrant interactions with key enzymes of the tricarboxylic acid (TCA) cycle, which lead to protein aggregation, loss of iron-sulfur cluster proteins, and proteotoxic stress, ultimately leading to cell death. Recent studies have revealed that Cu dyshomeostasis and cuproptosis are intricately linked to the pathological progression of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Wilson's disease (WD), and Menkes disease (MD). In this review, we systematically elucidate the systemic Cu metabolism, the molecular mechanisms of cuproptosis, and its intricate interplay with different neurodegenerative disorders. We also examined the relationship between cuproptosis and other types of cell death. Finally, we discuss therapeutic strategies targeting cuproptosis and Cu dyshomeostasis to combat neurodegenerative diseases and propose potential directions for future research.
    Keywords:  cell death; copper; copper homeostasis; cuproptosis; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnagi.2025.1688554
  13. JACS Au. 2025 Oct 27. 5(10): 4916-4935
    Repulsive vs Attractive Crowding Distinctly Regulate TDP-43 Condensates through Region-specific Structural Dynamics.
    Guoqing Zhang, Cibo Feng, Xiakun Chu.
      TAR DNA-binding protein 43 (TDP-43) is crucial for RNA processing and nucleocytoplasmic transport, and its pathological aggregation marks neurodegenerative disease. The intrinsically disordered, prion-like C-terminal domain (CTD) drives liquid-liquid phase separation (LLPS). Using residue-level coarse-grained simulations, we systematically examine how distinct macromolecular crowding environments, including repulsive (steric) and attractive (interaction-based) crowding conditions, influence the phase behavior and internal organization of TDP-43 CTD condensates. Both crowder types preserve correlations between single-chain compaction, dimerization propensity, and macroscopic phase separation, yet act through different mechanisms: repulsive crowders promote condensation via excluded-volume entropic stabilization, whereas attractive crowders modulate assembly through competitive enthalpic interactions. Region-specific spatial and orientation analyses reveal a robust internal architecture in which α-helices are enriched in the condensate interior (aligned roughly parallel to the interface) while intrinsically disordered regions (IDRs) populate the surface with broader, outward-facing orientations. Beyond these baseline trends, our region-specific orientation maps and contact-relaxation metrics show that the character of crowding actively resculpts condensate organization: repulsive crowders compact and centralize the helical network into a single dense core layer, whereas attractive crowders redistribute helices toward the interface by sequestering contacts. This establishes a structure-dynamics decoupling with strong but short-lived helix-helix contacts versus weaker yet more persistent IDR-IDR contacts, reconciling core stabilization with interfacial fluidity. Our results define crowding class as a tunable control knob for region-specific redistribution and dynamics, suggesting testable readouts and offering mechanistic links to physiological modulators such as RNA stoichiometry, ATP levels, chaperone engagement, and client size/permeability. Collectively, our findings uncover a regulatory principle by which macromolecular crowding modulates TDP-43 condensation through distinct entropic and enthalpic contributions, offering key mechanistic insights into condensate formation and dysregulation relevant to neurodegenerative diseases.
    Keywords:  biomolecular condensates; intrinsically disordered proteins; liquid−liquid phase separation; macromolecular crowding; protein−protein interactions; structure-dynamics relationship
    DOI:  https://doi.org/10.1021/jacsau.5c00876
  14. Int J Mol Sci. 2025 Oct 17. pii: 10122. [Epub ahead of print]26(20):
    Aggregation Characteristics of Tau Phosphorylated by Various Kinases as Observed by Quantum Dot Fluorescence Imaging.
    Eisuke Ishibashi, Koki Araya, Kota Nakamura, Keiya Shimamori, Koji Uwai, Masahiro Kuragano, Kiyotaka Tokuraku.
      This study focused on the abnormal phosphorylation of tau and its aggregation process, characteristic of Alzheimer's disease, and aimed to compare the morphology and formation process of phosphorylated tau aggregates produced by four kinases: Cdk5/p25, GSK3β, MARK4, and p38α. Using quantum dots for 2D and 3D structural analysis, tau aggregates were confirmed in non-phosphorylated tau (non p-tau), as well as tau phosphorylated by GSK3β and MARK4. Aggregation initiation times were observed around 72 h for non-p-tau, and around 96 h for GSK3β and MARK4 phosphorylated tau. The thickness of non-p-tau aggregates was approximately 11 μm, while GSK3β aggregates were significantly thicker (13 μm) and exhibited increased density. TEM analysis suggested that tau forming wavy filaments was less prone to forming large aggregates. ThT assays and CD spectra showed an increased β-sheet structure for all kinases. Non-p-tau and GSK3β exhibited an increased right-twisted β-sheet structure, while Cdk5/p25, MARK4, and p38α showed an increased left-twisted β-sheet structure. The direct correlation between kinase activity and tau aggregate morphology revealed in this study provides a potential mechanistic basis for understanding disease heterogeneity and establishing novel therapeutic targets for AD specifically or for other neurodegenerative diseases as well.
    Keywords:  Cdk5/p25; GSK3β; MARK4; kinase; p38α; quantum dots; tau; tau fibrils
    DOI:  https://doi.org/10.3390/ijms262010122
  15. Brain Behav. 2025 Nov;15(11): e71023
    Aggregation and Propagation of α-Synuclein in Parkinson's Disease: A Bibliometric Perspective.
    Xinyue Zhang, Yizhao Ma, Ge Gao, Qihui Wu.
       INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the aggregation and propagation of alpha-synuclein (α-syn), processes that contribute to neuronal dysfunction and cell death. Although substantial progress has been made in understanding α-syn pathology, a comprehensive bibliometric evaluation of global trends in this field remains lacking. This study aims to systematically map the research landscape surrounding α-syn aggregation and propagation in PD, offering insights into its molecular mechanisms and clinical relevance.
    METHODS: A bibliometric analysis was conducted using data retrieved from the Web of Science Core Collection (WoSCC) spanning 2005 to 2024. The data were processed and analyzed with R-Bibliometrix, VOSviewer, and CiteSpace to quantify publication trends, international collaborations, influential authors and institutions, journal impact, and keyword co-occurrence networks.
    RESULTS: A total of 3220 relevant articles were identified. The number of annual publications steadily increased, reflecting growing scholarly interest. The United States, China, and the United Kingdom emerged as leading contributors. Robust international collaborations were observed, especially among Western countries, with the University of California System identified as the most prolific institution. Two primary thematic clusters were revealed: (1) "aggregation," focusing on the roles of "mitochondria" and "lysosomes," and (2) "propagation," highlighting the involvement of "exosomes" and "microglia." Emerging research frontiers included "biomarkers" and "neuroinflammation," with a recent trend shifting toward studies on the propagation of α-syn.
    CONCLUSION: This study underscores a paradigm shift in PD research from α-syn aggregation to propagation, emphasizing the significance of exosomes, microglia, and systemic inflammation in disease pathogenesis. These findings provide a comprehensive roadmap for future research, highlighting the need for interdisciplinary collaboration and the development of targeted therapeutic strategies.
    Keywords:  Parkinson's disease; aggregation; bibliometric analysis; propagation; α‐synuclein
    DOI:  https://doi.org/10.1002/brb3.71023
  16. Sci Rep. 2025 Oct 29. 15(1): 37776
    Unveiling the phenylalanine coaggregation mechanism for a deep understanding of phenylketonuria disease.
    Haruna L Barazorda-Ccahuana, Francesc Mas, Sergio Madurga.
      The abnormal accumulation of phenylalanine is a defining feature of phenylketonuria (PKU) and is Linked to the formation of toxic, amyloid-like fibrils. To investigate the molecular mechanisms underlying this aggregation, we performed all-atom molecular dynamics simulations of zwitterionic phenylalanine at physiological temperature. Systems with varying phenylalanine concentrations were simulated over 500 ns to assess aggregation dynamics, structural stability, and non-covalent interactions. Our results show that phenylalanine rapidly self-assembles into fibrillar structures stabilized by hydrogen bonding and π-π stacking. Higher concentrations led to more compact aggregates, as indicated by radial distribution functions and solvent-accessible surface area analyses. We further examined the coaggregation of alanine with phenylalanine fibrils and found that alanine preferentially binds to zwitterionic terminal regions via hydrogen bonds. This interaction may contribute to the enhanced toxicity of phenylalanine aggregates. These findings provide molecular-level insights into phenylalanine aggregation in PKU and support the development of strategies to mitigate its pathological effects.
    DOI:  https://doi.org/10.1038/s41598-025-19843-5
  17. Langmuir. 2025 Oct 31.
    Aloe Vera Inhibits Protein Fibrillation: Mechanistic Biophysical Evaluation.
    Anu Jain, Nand Kishore.
      The aggregation of proteins and the formation of amyloid fibrils as a result of protein misfolding are thought to be strongly linked to neurodegenerative disorders, including those driven by infectious prions, Alzheimer's disease, and Parkinson's disease, to name only a few. The rapid discovery of inhibitors that prevent protein aggregation has aided in the development of therapeutic approaches for these conditions. Plant-based extracts and chemical substances have become intriguing sources of potential inhibitors since they can be used as particular pharmaceuticals at greater doses or as nutraceuticals as part of a healthy diet. Succulent plants like aloe vera have long been valued for their medicinal and healing qualities. This research focuses on the inhibition of hen egg white lysozyme fibrillation using aloe vera extract. To verify fibril formation and assess the inhibitory potential of aloe vera, an integrated approach involving calorimetric, spectroscopic, and microscopic techniques was employed. Employing a variety of methods, it was found that aloe vera promotes the thermal and structural stability of proteins while inhibiting the formation of fibrils. Furthermore, aloin, a significant bioactive component of aloe vera, was also studied for its anti-fibrillogenic properties and proven to efficiently prevent the formation of fibrils. Aloin demonstrated effective inhibition of protein fibrillation, likely through hydrophobic and electrostatic interactions. With the growing preference for natural products due to their reduced side effects, this study highlights the potential of plant-derived therapeutics as promising inhibitors of protein aggregation.
    DOI:  https://doi.org/10.1021/acs.langmuir.5c03925
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