bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–03–01
fifteen papers selected by
Verena Kohler, Umeå University
  1. Structural analysis of the asymmetric interaction between amyloid β42 and α-Synuclein: Amyloid β42 oligomers promote α-synuclein aggregation while α-synuclein inhibits amyloid β42 aggregation.
  2. CPEB3 selectively inhibits α-synuclein aggregation without modulating TDP-43 pathology.
  3. TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.
  4. Modulation of α-Synuclein Oligomer and Aggregate Populations by pH and Metal Ions.
  5. Seeing the Unseen: Super-Resolution Microscopy in Protein Aggregation Research.
  6. Discovery of TDP-43 aggregation inhibitors via a hybrid machine learning framework.
  7. Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
  8. Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates.
  9. Breaking β-sheets in FUS prion-like domain preserves phase separation and function but prevents aggregation and toxicity.
  10. Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau.
  11. Machine learning-assisted screening of small-molecule drugs for suppressing protein aggregation and ROS generation based on ECL and CV dual-mode signals amplified by DNA.
  12. Multifaceted performances of α-synuclein in health and neurological diseases.
  13. Editorial: Proteostasis disruption in neurodegenerative disorders: mechanisms and treatment strategies.
  14. Time-Resolved SAXS Reveals Distinct Millisecond Metal-Induced Conformational Dynamics of Monomeric α-Synuclein.
  15. Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.
  1. Biochem Biophys Res Commun. 2026 Feb 19. pii: S0006-291X(26)00270-6. [Epub ahead of print]809 153506
    Structural analysis of the asymmetric interaction between amyloid β42 and α-Synuclein: Amyloid β42 oligomers promote α-synuclein aggregation while α-synuclein inhibits amyloid β42 aggregation.
    Koki Araya, Kota Nakamura, Eisuke Ishibashi, Taro Q P Noguchi, Masahiro Kuragano, Kiyotaka Tokuraku.
      Amyloid β (Aβ) and α-synuclein (α-syn) have traditionally been recognized as the major causative proteins in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. However, AD and PD share many common pathogenic mechanisms and exhibit overlapping pathological features. Furthermore, multiple studies have reported the coexistence of Aβ and α-syn within the same pathological regions in individual patients, suggesting that such pathological coexistence is involved in disease progression and pathogenesis. However, the detailed mechanisms by which Aβ and α-syn influence each other and modulate their aggregation dynamics remain unclear. We previously established a method to observe the aggregation processes of Aβ and α-syn in two and three dimensions by utilizing the affinity between quantum dots (QDs) and amyloid aggregates, using fluorescence microscopy and confocal laser scanning microscopy. In this study, we used QD imaging, thioflavin T (ThT) fluorescence assays, and transmission electron microscopy (TEM) to evaluate in detail how Aβ42 and α-syn affect each other's aggregation behaviors. We found that 1 μM Aβ42 monomers did not affect the aggregation of 20 μM α-syn, whereas 1 μM Aβ42 oligomers significantly promoted 20 μM α-syn aggregation. In contrast, 1-10 μM α-syn inhibited the aggregation of 20 μM Aβ42 in a concentration-dependent manner, with α-syn polymers showing a stronger inhibitory effect than α-syn monomers. Taken together, these results demonstrate an asymmetry in their mutual effects on aggregation under the experimental conditions examined in this study: Aβ42 oligomers promote α-syn aggregation, whereas α-syn inhibits Aβ42 aggregation, particularly in its polymeric form.
    Keywords:  Alzheimer's disease; Amyloid β42; Cross-talk; Parkinson's disease; Quantum dots; α-synuclein
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153506
  2. FEBS Lett. 2026 Feb 24.
    CPEB3 selectively inhibits α-synuclein aggregation without modulating TDP-43 pathology.
    Ann Teres Babu, Mufeeda Farhana A, Harsha Varthini Periasamy, Vinesh Vijayan.
      Abnormal accumulation of misfolded proteins is a hallmark of neurodegenerative diseases. Amyloid aggregation of α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) contributes to Parkinson's disease and frontotemporal dementia, respectively. The heterotypic aggregates are increasingly recognized as highly cytotoxic. Given the frequent co-occurrence of α-Syn, TDP-43, and tau pathologies, we examined whether the first prion-like domain (PRD1) of CPEB3 modulates α-Syn and TDP-43 aggregation. Nuclear magnetic resonance (NMR) relaxation experiments revealed a direct interaction between PRD1 and the amyloid core of α-Syn, suppressing its aggregation, while phase separation assays showed delayed liquid-liquid phase separation (LLPS) -mediated α-Syn aggregation. In contrast, no interaction was detected with the C-terminal domain of TDP-43 (TDP-43CTD), indicating selective inhibition of α-Syn aggregation by PRD1.
    Keywords:  NMR spectroscopy; Parkinson's disease; TDP‐43; aggregation inhibitor; phase separation; protein–protein interaction; α‐synuclein
    DOI:  https://doi.org/10.1002/1873-3468.70308
  3. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705390. [Epub ahead of print]
    TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.
    Ziyan He, Jiechao Zhou, Rongzhen Zhang, Fei Meng, David W Nauen, Juan C Troncoso, Paul F Worley, Wenchi Zhang.
      Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.
    DOI:  https://doi.org/10.64898/2026.02.11.705390
  4. Biomolecules. 2026 Feb 20. pii: 326. [Epub ahead of print]16(2):
    Modulation of α-Synuclein Oligomer and Aggregate Populations by pH and Metal Ions.
    Ananya Nair, Punarvash Mitta, Lathan Lucas, Josephine C Ferreon, Allan Chris M Ferreon.
      α-Synuclein (α-syn) aggregation underlies synucleinopathies, yet the physicochemical determinants that govern which assembly states form under defined solution conditions remain incompletely resolved. Here, we examine how pH and metal ions reshape α-syn self-assembly. Across acidic and physiological pH conditions, α-syn populates monomeric, nanoscale oligomeric, and mesoscale aggregate states whose relative abundances evolve over time. Fluorescence microscopy reveals robust mesoscale assembly at pH 5, minimal aggregation at pH 7, and transient assemblies at pH 3, highlighting the limitations of imaging-based detection alone. Therefore, we use dynamic light scattering (DLS) to resolve oligomeric populations and quantify pH-dependent redistribution of assembly mass. Toxicity-mitigating modulators altered α-syn assembly in a strongly pH-dependent manner. Anle138b increased the abundance of oligomeric species at low pH, whereas EGCG produced divergent effects at pH 5 and pH 3. We further examined the effects of metal ions, finding that Fe3+ stabilized higher-order assemblies under acidic conditions, Cu2+ delayed assembly at pH 5 while enhancing aggregation at pH 3, and Zn2+ increased oligomerization primarily at low pH. Overall, these results demonstrate that α-syn assembly is highly sensitive to coupled effects of pH, metal chemistry, and time.
    Keywords:  metal ions; neurodegeneration; pH; protein aggregation; protein self-assembly; synucleinopathies; α-synuclein
    DOI:  https://doi.org/10.3390/biom16020326
  5. Chem Biomed Imaging. 2026 Feb 23. 4(2): 116-129
    Seeing the Unseen: Super-Resolution Microscopy in Protein Aggregation Research.
    Molly J M Turner, Junsheng Chen, Nikos S Hatzakis, Min Zhang.
      Super-resolution microscopy surpasses the diffraction limit and enables the visualization of biomolecular structures with unprecedented detail. These techniques have been widely used in many scientific areas, including cell biology, genomics, microbiology, and material science. In the field of protein aggregation, a process intimately linked to numerous neurodegenerative diseases, the high spatial resolution of super-resolution microscopy enables the direct observation of the fine structure of different species, ranging from small oligomers to mature aggregates, providing insights into molecular aggregation mechanisms and the pathology of neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's disease. In this review, we outline the principles of three major super-resolution microscopy techniques, including stimulated emission depletion (STED), structured illumination microscopy (SIM), and single-molecule localization microscopy (SMLM), and compare their respective strengths and limitations in studying protein aggregation. We then highlight the recent applications of these techniques in studying protein aggregation, with a focus on aggregate morphology, dynamic formation processes, and interactions with cellular components.
    Keywords:  aggregation pathways; distribution; morphology; neurodegenerative disease; pathology; protein aggregation; super-resolution microscopy; toxicity
    DOI:  https://doi.org/10.1021/cbmi.5c00041
  6. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705375. [Epub ahead of print]
    Discovery of TDP-43 aggregation inhibitors via a hybrid machine learning framework.
    Sofia Kapsiani, Sulay Vora, Ana Fernandez-Villegas, Clemens F Kaminski, Nino F Läubli, Gabriele S Kaminski Schierle.
      TAR DNA-binding protein 43 (TDP-43) aggregation is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Recent therapeutic efforts have highlighted the potential of small molecules capable of inhibiting TDP-43 aggregation; however, no effective treatments currently exist. Here, we developed a hybrid machine learning approach combining graph neural network (GNN) embeddings with traditional chemical descriptors and biological target annotations. Using XGBoost as the final classifier enabled model interpretability through SHAP analysis, allowing the identification of key chemical features and target annotations associated with TDP-43 anti-aggregation activity. Complementary Monte Carlo Tree Search analysis highlighted specific chemical substructures linked to predicted activity. By screening an external library of 3,853 small molecules, the model identified two compounds not previously evaluated against TDP-43 aggregation, namely berberrubine and PE859. Molecular docking analysis revealed that both compounds interact favourably with the TDP-43 RNA recognition motif (RRM) domain through distinct binding modes. Experimental validation showed that both compounds significantly reduced TDP-43 aggregation in HEK cells. Further testing in Caenorhabditis elegans expressing human TDP-43 demonstrated that PE859 significantly rescued locomotor defects, while berberrubine showed partial improvement. This work establishes a hybrid machine learning approach for accelerating small molecule drug discovery, yielding two promising therapeutic candidates for TDP-43 proteinopathies.
    DOI:  https://doi.org/10.64898/2026.02.12.705375
  7. Res Sq. 2026 Feb 16. pii: rs.3.rs-8780765. [Epub ahead of print]
    Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
    Zoya R Bangash, Hiroyoshi Matsui, Bedri Ranxhi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou.
      Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression attenuated α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30 , Uch-L5R , RNF185 , and the mitochondrial ornithine carrier SLC25A15 . At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions and reduced mitochondrial accumulation of α-Syn. Our findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and altered mitochondrial-associated proteostasis during α-Syn expression.
    DOI:  https://doi.org/10.21203/rs.3.rs-8780765/v1
  8. bioRxiv. 2026 Feb 18. pii: 2026.02.17.706203. [Epub ahead of print]
    Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates.
    Carolyn J Decker, Kathleen McCann, Evan Lester, James Pratt, Meaghan Van Alstyne, Yuchen Wang, Roy Parker.
      Tau aggregates contribute to multiple neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease (AD). In models of tauopathy and in patient tissue, tau aggregates can form in the cytoplasm, perinuclear region, and nucleus. Using a HEK293T tau biosensor system, we identified that cytoplasmic tau aggregates formed first, followed by perinuclear-ring-like tau assemblies, and then nuclear tau aggregates formed in nuclear speckles. Nuclear tau aggregates only form in cells with pre-existing cytoplasmic tau aggregates and mostly form independently of cells traversing mitosis. Finally, nuclear tau aggregates do not contain exogenous tau seeds and arise by a secondary seeding event dependent on VCP. Nuclear tau aggregates inhibit mRNA export and show a twofold increase in poly-adenylated mRNAs in the nucleus. Together, these findings indicate that nuclear tau aggregation alters RNA biogenesis and occurs by a secondary seeding event from cytoplasmic tau aggregates, which could contribute to tau pathology.
    DOI:  https://doi.org/10.64898/2026.02.17.706203
  9. bioRxiv. 2026 Feb 18. pii: 2026.02.17.706410. [Epub ahead of print]
    Breaking β-sheets in FUS prion-like domain preserves phase separation and function but prevents aggregation and toxicity.
    Noah Wake, Juan Alcalde, Daniel Jutzi, Anjali Bajaj, Sukhleen Kour, Mayur Barai, Shuo-Lin Weng, Samara Cummings, Tongyin Zheng, Eric N Anderson, Szu-Huan Wang, Ryan Puterbaugh, Daryl A Bosco, Benjamin S Schuster, Jeetain Mittal, Udai Bhan Pandey, Marc-David Ruepp, Nicolas L Fawzi.
      The RNA-binding protein Fused in Sarcoma (FUS) undergoes phase separation associated with RNA processing. However, the prion-like low complexity (LC) domain of FUS forms solid-like aggregates in neurodegenerative diseases. Whether the formation of β-sheet structure associated with pathology is also physiologically/functionally relevant is debated. Similarly, if mislocalization alone or concomitant aggregation is responsible for FUS gain-of-function toxicity remains to be probed. Here, we introduce β-sheet breaking proline residues into FUS LC with the goal of preventing cross-β-driven aggregation without disrupting essential functions and phase separation. β-sheet-deficient FUS variants maintain native-like global motions, disorder, and phase separation, but no longer show a liquid-to-solid transition (LST). Biochemical partitioning, cellular localization, and auto- and cross-regulatory functions of FUS all remain essentially unchanged. Conversely, FUS-induced neurodegeneration in several Drosophila models is drastically reduced. These findings suggest a strategy for mitigating disease-related toxicity through backbone structure modulation to prevent prion-like domain protein aggregation.
    GRAPHICAL ABSTRACT:
    SUMMARY: The RNA-binding protein Fused in Sarcoma (FUS) undergoes phase separation as part of its physiological function but can aberrantly aggregate into solid-like assemblies in amyotrophic lateral sclerosis and frontotemporal dementia. To dissect the role of β-sheets in both function and pathological transition, we engineered β-sheet-preventing FUS variants via targeted proline residue insertions in the prion-like disordered region. These variants retained native structure, motions, and phase behavior yet showed dramatically reduced aggregation, both as an isolated prion-like domain and in full-length FUS. Crucially, these variants maintained a panel of FUS cellular functions that depend on FUS condensation but prevented FUS toxicity in fly models of neurodegeneration. Our findings implicate β-sheets as key drivers of FUS condensate maturation and neuronal toxicity, highlighting β-sheet modulation as a therapeutic strategy against FUS-related neurodegeneration.
    HIGHLIGHTS: Targeted proline additions disrupt β-sheet formation in FUS without altering native conformations, dynamics, or phase separation behaviorβ-sheet-deficient FUS variants prevent aggregation and liquid-to-solid transitions while retaining key biological functions In vivo models reveal attenuated toxicity of β-sheet-deficient FUS in Drosophila β-sheets are identified as central drivers of condensate maturation and neuronal death, offering a therapeutic entry point for modulating prion-like domain pathology.
    DOI:  https://doi.org/10.64898/2026.02.17.706410
  10. Dis Model Mech. 2026 Feb 23. pii: dmm.052295. [Epub ahead of print]
    Impairment of neuronal activity occurs at the early stages of the aggregation cascade of Aβ1-42 and mutant Tau.
    Franziska Hirsch, Nino Läubli, Anushree Kelkar, Mira Sleiman, Yvonne Woitzat, Christian Gallrein, Vanessa Gumz, Gurleen Kaur Kalsi, Ana Fernandez-Villegas, Gabriele Kaminski Schierle, Janine Kirstein.
      Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of Aβ and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. For that we used a neuronal GCaMP reporter to monitor fluctuations in Ca2+ and developed microfluidic devices to immobilize nematodes to non-invasively assess neuronal activity. Our findings reveal that expression of both Aβ and Tau lead to significant reductions in neuronal activity and function in young adult animals preceding the accumulation of amyloid aggregates. Notably, Aβ expression and aggregation in muscle tissue produced comparable detrimental effects on neuronal activity as its expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through the propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight that TauP301L,V337M has a significant impact on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.
    Keywords:  Abeta; Aging; Alzheimers disease; C. elegans; Neurodegeneration; Tau
    DOI:  https://doi.org/10.1242/dmm.052295
  11. Chem Sci. 2026 Feb 02.
    Machine learning-assisted screening of small-molecule drugs for suppressing protein aggregation and ROS generation based on ECL and CV dual-mode signals amplified by DNA.
    Jiaqi Shi, Wenxiu Zhu, Jingyu Yan, Cong Xiao, Huiqin Yao, Lingchen Meng, Hongyun Liu, Lanqun Mao.
      Screening of small-molecule drugs to suppress both protein aggregation and reactive oxygen species (ROS) generation is critical for developing therapies for neurodegenerative diseases (NDs). However, existing methods are limited to characterizing only a single pathological feature (either protein aggregation or ROS generation) in a single measurement. Herein, taking α-synuclein (α-Syn) as the template protein, we developed a dual-mode electrochemical sensing platform for concurrently monitoring protein aggregation and ROS generation characteristics. A gold electrode functionalized with α-Syn via self-assembled monolayers (SAMs) was constructed as the sensing platform, realizing both ordered α-Syn immobilization and monitoring of metal ion (e.g., Cu(ii))-driven aggregation. This was accomplished by synchronously recording the electrochemiluminescence (ECL) and cyclic voltammetry (CV) dual responses of the tris(2,2'-bipyridine) ruthenium(ii) (Ru(bpy)3 2+) reporter in a single integrated assay. The catalysis of DNA oxidation by Ru(bpy)3 2+ enables the amplification of ECL and CV dual-mode signals, which increased the detection sensitivity for both aggregation and ROS generation accompanied by the α-Syn - Cu(ii) complex. Machine learning algorithms were then utilized to analyze ECL and CV responses of small molecules with known drug effects. This analysis culminated in the development of a linear discriminant analysis (LDA) screening model, which enabled the assessment of drug efficacy against the two pathological features. The predictive capability of the screening model was verified through transmission electron microscopy (TEM), cell viability and intracellular aggregation studies. This model was further successfully applied to assess two previously unexplored small molecules: diethylenetriaminepentaacetic dianhydride (DTPA) and deferiprone. Collectively, this dual-mode sensing platform, integrating DNA-amplified monitoring of protein aggregation and ROS generation, enables the robust establishment of a machine learning-assisted small-molecule drug screening model, offering a novel approach for the in vitro characterization of protein-related pathological features.
    DOI:  https://doi.org/10.1039/d5sc08658b
  12. Neuroscience. 2026 Feb 23. pii: S0306-4522(26)00128-4. [Epub ahead of print]
    Multifaceted performances of α-synuclein in health and neurological diseases.
    Min Wang, Yourui Xu, Shengming Wang, Jiayan Liang, Xiangwen Cui, Chong Zhang, Junli Yang, Liyuan Sun, Mingyue Jin.
      The misfolding and accumulating α-synuclein (αSyn) is a central pathological hallmark of various neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Under physiological conditions, αSyn essential for normal synaptic functions primarily through its regulation of synaptic vesicle trafficking, clustering, and neurotransmitter release. However, in disease states, the accumulation of pathological αSyn disrupts intracellular proteostasis, by impairing the ubiquitin-proteasome system, autophagy-lysosomal degradation pathway and endo-lysosomal pathway. This disruption ultimately leads to synaptic dysfunction and neuronal death. Here, we summarize current insights into the physiological and pathological roles of αSyn, focusing on its post-translational modifications, dysregulation of protein quality control systems, prion-like cell-to-cell propagation, and liquid-liquid phase separation. We also discuss emerging therapeutic strategies that target abnormally aggregated αSyn. A comprehensive understanding of αSyn's multifaceted mechanisms is therefore critical for developing novel diagnostic biomarkers and effective therapeutics for α-synucleinopathies.
    Keywords:  Parkinson’s disease; Post-translational modifications of α-synuclein; Protein homeostasis; α-Synuclein
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.031
  13. Front Mol Neurosci. 2026 ;19 1796704
    Editorial: Proteostasis disruption in neurodegenerative disorders: mechanisms and treatment strategies.
    Jonasz Jeremiasz Weber, Hiroaki Taniguchi, Maxim Sokolov.
      
    Keywords:  autophagy; mitochondrial proteostasis; molecular chaperones and protein-unfolding ATPases; neurodegeneration; proteases; proteasome; protein aggregation; transcription of proteasomal genes
    DOI:  https://doi.org/10.3389/fnmol.2026.1796704
  14. Adv Sci (Weinh). 2026 Feb 27. e12293
    Time-Resolved SAXS Reveals Distinct Millisecond Metal-Induced Conformational Dynamics of Monomeric α-Synuclein.
    Rebecca Sternke-Hoffmann, Miriam Dos Santos Pinto, Xue Wang, Jinghui Luo.
      Transition metal ions have been implicated in modulation the conformational behavior and aggregation of WT α-synuclein (WT-αSyn), associated with Parkinson's disease pathology. Nevertheless, the initial structural rearrangements that drive aggregation are not fully understood. Here, we employed time-resolved small-angle X-ray scattering (TR-SAXS) in a microfluidic setup to investigate the structural dynamics of monomeric WT-αSyn upon interaction with Mn2 +, Fe3 +, Cu2 +, and Zn2 +. Using Guinier analysis, GNOM, and Ensemble Optimization Method (EOM), we resolved distinct, metal-specific conformational transitions on the sub-second timescale. Fe3 + induced rapid and sustained compaction of αSyn, while Cu2 + promoted extended and heterogeneous conformations, expanding the C-terminal domain, and disrupting global folding. In contrast, Mn2 + and Zn2 + led to more gradual, domain-specific compaction. Fractal dimension analysis and hierarchical clustering further revealed Fe3 + and Zn2 + enriched compaction states, while Cu2 + favored intermediate species potentially linked to early aggregation. These findings highlight how metal ion binding differentially and initially reshape the conformation ensemble of WT-αSyn, offering mechanistic insight into metal-induced misfolding pathways relevant to synucleinopathies.
    Keywords:  conformational dynamics; intrinsically disordered proteins; metal ions; protein‐metal interaction; time‐resolved SAXS; α‐synuclein
    DOI:  https://doi.org/10.1002/advs.202512293
  15. Biochem Pharmacol. 2026 Feb 20. pii: S0006-2952(26)00162-0. [Epub ahead of print]248 117831
    Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.
    Xiuling Zhao, Liping Pu, Xuhui Zeng, Junyu Nie.
      Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.
    Keywords:  Importin α/β; NLS; Nuclear import; Pathogenesis; Proteostasis
    DOI:  https://doi.org/10.1016/j.bcp.2026.117831
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