bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–05–03
thirteen papers selected by
Verena Kohler, Umeå University
  1. Modulation of biomolecular condensation of alpha-synuclein variants by eprodisate.
  2. Cryo-EM methods to study binding between amyloid fibrils and chemical compounds.
  3. Stimuli-Chromic Oxazolidine Derivatives as Highly Efficient Molecular Probes for Monitoring Fibrillation Kinetics and Intracellular Detection of Amyloid Fibrils.
  4. Interaction between Poly(ADP-ribose) polymerase-1 and α-synuclein pathology in Parkinson's disease.
  5. Identification of Secondary Nucleation Inhibitors of Amyloid-β Aggregation by Cellular Selection of a SICLOPPS Library.
  6. Differential effects of α-Synuclein monomers and seeds on the material properties of Tau condensates.
  7. Amyloid extraction from neurodegenerative disease tissues for structural studies.
  8. From stability to pathology: protein degradation pathways underlying synaptic proteins in neurological diseases.
  9. Two-dimensional FTIR methods on amyloid aggregation and folding pathways.
  10. Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.
  11. Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.
  12. mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.
  13. A coherent structural picture of the interaction of Tau with tubulin provides a link to its aggregation.
  1. Commun Chem. 2026 Apr 27.
    Modulation of biomolecular condensation of alpha-synuclein variants by eprodisate.
    Soumojit Biswas, Nimisha A Mavlankar, Venkataharsha Panuganti, Asish Pal, Ipsita Roy.
      Aggregation of α-synuclein (α-SYN) into amyloid structures is closely associated with Parkinson's disease (PD). Prevention of α-SYN aggregation has been validated as a key strategy to manage PD. α-SYN undergoes liquid-liquid phase separation (LLPS) via biomolecular condensation that facilitates nucleation and amyloid formation in liquid droplets. In this work, the effect of eprodisate (a glycosaminoglycan mimetic) on the formation of biomolecular condensates by α-SYN and its pathology-relevant variants has been investigated. Eprodisate affected the formation of α-SYN condensates, increased the fluidity inside droplets and inhibited α-SYN from turning into amyloid. It also attenuated aggregation of α-SYN variants in the presence of chondroitin sulphate. Eprodisate inhibited phase separation, hydrogel formation and amyloid aggregation of PD-related α-SYN A30P, α-SYN S129D and C-terminal truncated variants. It reduced oxidative stress, decreased α-SYN-positive aggregates and increased cell survival. These findings show that eprodisate may be explored further as an ameliorative therapy in PD.
    DOI:  https://doi.org/10.1038/s42004-026-02032-4
  2. Methods Enzymol. 2026 ;pii: S0076-6879(26)00037-6. [Epub ahead of print]729 107-144
    Cryo-EM methods to study binding between amyloid fibrils and chemical compounds.
    Qinyue Zhao, Kaien Liu, Dan Li, Cong Liu.
      Amyloid fibrils formed by amyloid proteins such as α-synuclein (α-syn), Amyloid-β (Aβ) and Tau are central to the pathology of neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease (AD). Structural elucidation of fibril-ligand interactions is essential for the rational design of imaging probes and therapeutic inhibitors targeting these pathological aggregates. Here, we present a comprehensive cryo-electron microscopy (cryo-EM)-based workflow for modeling small-molecule binding to amyloid fibrils, with a focus on α-syn-ligand complexes. The protocol integrates optimized fibril sample preparation, helical reconstruction, and iterative 2D/3D classification to yield high-resolution density maps suitable for atomic modeling. Ligands are incorporated by generating coordinates from SMILES strings and restraint files from Phenix eLBOW, followed by manual docking and real-space refinement. Using CCA-α-syn complex as a case study, we demonstrate precise ligand placement into specific fibril binding sites (the C-pocket, N-pocket, and a back-surface groove of the fibril core distinct from typical globular protein pockets). Subsequent structural refinement preserved key interaction features, including π-π stacking and side-chain hydrogen bonding. Validation metrics confirm the stereochemical integrity and good model-to-map fit of the final fibril-ligand complex structures. Overall, this workflow enables accurate modeling of ligand engagement with amyloids even at ∼3-4 Å resolution and provides a scalable framework for structure-guided ligand discovery in neurodegenerative disease research.
    Keywords:  Amyloid fibril; Chemical ligand; Cryo-EM; Neurodegenerative diseases; α-Synuclein
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.029
  3. Biochemistry. 2026 Apr 27.
    Stimuli-Chromic Oxazolidine Derivatives as Highly Efficient Molecular Probes for Monitoring Fibrillation Kinetics and Intracellular Detection of Amyloid Fibrils.
    Farimah Tondkar, Foad Rezaeifar, Mahdieh Ghorbani, Amin Abdollahi, Ali Akbar Meratan.
      Misfolding and aggregation of proteins into amyloid fibrils is a main pathological hallmark of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Thus, development of probes with the potential to cross biological membranes and detect intracellular aggregates is an area of intense research. In the present study, we have reported the synthesis of two new stimuli-chromic oxazolidine derivatives (OX1 and OX2), with aggregation-induced emission (AIE) characteristics, for monitoring fibrillation kinetics and intracellular detection of amyloid fibrils. Although both probes are nonfluorescent in the presence of monomers and soluble oligomers, their binding to amyloid fibrils is accompanied by considerable red fluorescence. We suggest that changes in the polarity of the amyloid fibril microenvironment, caused by structural changes and exposure of hydrophobic regions during the fibrillation process, promote the selective binding and aggregation of these compounds on the surface of amyloid fibrils, leading to their considerable fluorescence emission. Cellular experiments indicate that both dyes are membrane-permeable without any significant cytotoxicity and can detect intracellular fibrils of α-synuclein and human insulin. Molecular docking studies suggest stronger binding affinity of OX2 than that of ThT for monomers and amyloid fibrils. In summary, we believe that properties such as intracellular detection of amyloid fibrils, red fluorescence without any significant interference with autofluorescence, and solid-state solvatochromic and AIE characteristics may distinguish OX1/OX2 from ThT and previously reported probes, making these compounds more suitable candidates for the detection of amyloid aggregates both in vitro and in vivo.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00806
  4. Front Neurosci. 2026 ;20 1774158
    Interaction between Poly(ADP-ribose) polymerase-1 and α-synuclein pathology in Parkinson's disease.
    Peng Zhang, Qinghua Li, Xiaojun Diao, Sihao Zeng.
      Poly(ADP-ribose) polymerase-1 (PARP-1) activation and α-synuclein (α-syn) aggregation are neuropathological hallmarks of Parkinson's disease. This review aims to summarize the extensive interplay between these two factors. PARP-1 induces conformational changes in α-syn through structural reorganization mediated by poly(ADP-ribose) (PAR). Stress conditions resulting from PARP-1 overactivation are involved in the post-transcriptional regulation of α-syn. Oxidative and nitrative stress triggered by PARP-1 overactivation participate in the post-translational modifications of α-syn. PAR also contributes to α-syn degradation pathways, thereby influencing α-syn levels. Conversely, α-syn indirectly promotes PARP-1-dependent cell death via reactive oxygen species (ROS), suggesting a possible link through cell death pathways. These findings indicate that intracellular PARP-1, its metabolic products, and α-syn are closely associated, leading to dopaminergic neuronal vulnerability and potentially creating a vicious cycle of toxicity in PD pathology.
    Keywords:  PARP-1; Parkinson’s disease; Poly(ADP-Ribose) Polymerase-1; Poly(ADP-ribose); neurodegeneration; oxidative stress; α-Synuclein
    DOI:  https://doi.org/10.3389/fnins.2026.1774158
  5. Chembiochem. 2026 Apr 28. 27(8): e202500908
    Identification of Secondary Nucleation Inhibitors of Amyloid-β Aggregation by Cellular Selection of a SICLOPPS Library.
    ByungUk Lee, Brian Flood, Emma Potter, Tina Wang.
      Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) aggregates. Soluble oligomers Aβ oligomeric intermediates (AβOs) generated during aggregation are hypothesized to be a neurotoxic species. Many cyclic peptides have been developed to inhibit Aβ aggregation but primarily target Aβ monomers and fibrils; few cyclic peptides selectively recognize AβOs. We selected a library of >107 cyclic peptides generated by the widely used split-intein mediated circular ligation of peptides and proteins (SICLOPPS) strategy for binders of AβOs. These selections identified cyclo-CRLISFF, which significantly delayed Aβ42 aggregation in vitro but displayed a mechanism inconsistent with inhibitors selectively targeting AβOs. To resolve this discrepancy, we tested whether intermediates formed during SICLOPPS cyclic peptide generation might also possess AβO binding activity. Our experiments showed that the CRLISFF sequence was active as an intein-bound intermediate which selectively targeted AβOs by inhibiting the secondary nucleation step of the Aβ42 aggregation cascade. This intermediate has not been previously examined in studies employing SICLOPPS and may present a convoluting factor when using this technology to generate cyclic peptide libraries. The CRLISFF motif also retained activity when transplanted onto an unrelated protein scaffold, suggesting that SICLOPPS sequences may be compatible with peptide grafting strategies used to create protein-based binders.
    Keywords:  amyloid; cyclic peptides; peptides; protein aggregation; split‐inteins
    DOI:  https://doi.org/10.1002/cbic.202500908
  6. bioRxiv. 2026 Apr 16. pii: 2026.04.14.718443. [Epub ahead of print]
    Differential effects of α-Synuclein monomers and seeds on the material properties of Tau condensates.
    Bineet Sharma, Jinying Wang, Priscilla Chinchilla Retana, Jean Baum, Zheng Shi.
      Tau and α-Synuclein (αSyn) frequently co-aggregate in various neurodegenerative disorders. Recently, Tau has been shown to form dynamic, liquid-like condensates that can recruit αSyn, and potentially serve as a precursor to pathological aggregation. However, the quantitative impact of αSyn on the material properties of these condensates remains elusive. Here, we measure the viscosity and interfacial tension of Tau condensates and determine how these properties are modulated by αSyn monomers and fibril seeds. We find that while both forms of αSyn partition efficiently into Tau condensates, they exert vastly different effects on the condensate's material state. The viscosity of Tau condensates remains unchanged in the presence of αSyn monomers at concentrations up to 200 µM, accompanied by a moderate reduction in the condensates' interfacial tension. In contrast, the addition of only 5 µM αSyn fibril seeds triggers rapid solidification of Tau condensates, manifested by a nearly 100-fold increase in condensate viscosity within one hour. These findings provide quantitative insights into condensate mechanics, highlighting the unique capacity of αSyn seeds to drive the liquid-to-solid transition of Tau condensates that may underlie the formation of pathological aggregates.
    DOI:  https://doi.org/10.64898/2026.04.14.718443
  7. Methods Enzymol. 2026 ;pii: S0076-6879(26)00040-6. [Epub ahead of print]729 1-33
    Amyloid extraction from neurodegenerative disease tissues for structural studies.
    Mohammed M Alhadidy, Tiara V Hinton, Katelyn N Ernst, Yang Yang.
      Amyloid aggregates are hallmarks of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Yet structural analysis of these brain-extracted filaments requires specialized extraction protocols that minimize structural perturbation while removing tissue matrix components. This chapter focuses on amyloid-β (Aβ) filaments, the primary component of senile plaques in AD, and presents three complementary methods for isolating these filaments from human brain tissues suitable for cryo-electron microscopy analysis. These methods have enabled high-resolution structural studies reaching 2.0-3.5 Å resolution and revealed distinct conformational polymorphs in AD and other neurodegenerative diseases. Method selection depends on tissue type, target filaments, and downstream analysis requirements, with comprehensive guidance provided for optimal protocol choice and implementation. The protocols demonstrate broad applicability beyond Aβ extraction, with successful adaptations provided for tau, α-synuclein, and TDP-43 extraction. Understanding these filamentous structures extracted with minimal perturbation is essential for developing targeted therapeutics and advancing structure-based drug design approaches for AD, PD, ALS, FTD, and other neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Amyloids; Aβ; Cryo-EM; Extraction method; Neurodegenerative diseases; Structural studies
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.032
  8. Neuroscience. 2026 Apr 29. pii: S0306-4522(26)00285-X. [Epub ahead of print]
    From stability to pathology: protein degradation pathways underlying synaptic proteins in neurological diseases.
    Yuanyuan Li, Xiao-Yu Hou, Yanmei Tao.
      Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the Ubiquitin-Proteasome System (UPS), autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically regulate the degradation of critical synaptic components from AMPA and NMDA receptors to scaffolds like PSD-95 and SHANK3. We further explore how autophagy, including chaperone-mediated and activity-dependent forms, contributes to synaptic remodeling and quality control. Crucially, dysfunction of synaptic degradation pathways is a common thread in neurodevelopmental and neurodegenerative disorders. We summarize evidence linking proteostatic malfunction to the pathogenesis of Alzheimer's disease (through impaired clearance of Aβ and tau), Parkinson's disease (via α-synuclein turnover), epilepsy, autism spectrum disorder, and ischemic injury. The review highlights how genetic mutations in degradation machinery or their synaptic targets converge to disrupt synaptic integrity and neural circuit function. By integrating findings from basic neurobiology and disease models, this review underscores the central importance of synaptic proteostasis and aims to identify critical regulatory molecules that retain potentials for diagnostic biomarkers and therapeutic targets for neurological disease.
    Keywords:  Autophagy-lysosomal pathway; Neurological diseases; Synaptic protein stability; Ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.04.025
  9. Methods Enzymol. 2026 ;pii: S0076-6879(26)00035-2. [Epub ahead of print]729 333-359
    Two-dimensional FTIR methods on amyloid aggregation and folding pathways.
    Michał Maj.
      This chapter explores the application of two-dimensional infrared (2DIR) spectroscopy to investigate amyloid aggregation mechanisms. It details experimental strategies, including site-specific isotope labeling, to monitor residue-level kinetics and transient intermediates in amyloids. The chapter further examines polarization-resolved 2DIR and cross-peak analysis for distinguishing coexisting fibril polymorphs and quantifying secondary nucleation events. Additionally, we highlight the ability of 2DIR to detect amyloid structures in tissues. Collectively, these advancements establish 2DIR as a precise, structure-specific tool for elucidating aggregation pathways in both solution and physiologically relevant contexts.
    Keywords:  2DIR spectroscopy; Amyloid aggregation; Amyloids; Dynamics; Secondary structure; Transient Intermediates; hIAPP
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.027
  10. Nat Commun. 2026 Apr 29.
    Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.
    Reut Bruck-Haimson, Hana Boocholez, Huadong Zhu, Adam Zaretsky, Irit Cohen, Xiaofeng Feng, Yong-Hong Yan, Meng-Qiu Dong, Ehud Cohen.
      The attachment of Post-Translational Modifications (PTMs) to proteins regulates their activities and stability. Here we utilized the nematode Caenorhabditis elegans to test whether UFMylation, a PTM which affects key biological functions, regulate aging and protein homeostasis (proteostasis). We find that lowering UFMylation extends lifespan and mitigates the toxicity of aggregation-prone proteins that underlie the development of neurodegenerative disorders in humans. Mass spectrometric analysis suggests that UFMylation of aging-regulating proteins, including of the nucleolar FIB-1-NOL-56 complex and the germline-resident proteins CAR-1 and CGH-1, governs proteostasis, probably across tissues. Functional analyses indicate that the proteostasis-regulating transcription factors DAF-16 and SKN-1 are crucial for the protective effects of reduced UFMylation. Counter-proteotoxic effect of reduced UFMylation are mediated by enhanced nascent protein quality control, reduced protein aggregation, and increased protein degradation by the ubiquitin-proteasome system. These insights highlight the important roles of PTMs in the regulation of proteostasis and point at research directions for the development of therapies for neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72479-5
  11. J Adv Res. 2026 Apr 26. pii: S2090-1232(26)00370-X. [Epub ahead of print]
    Physiological and pathological functions of TAF15 in neurodegenerative diseases and cancers.
    Congcong Liu, Lanxia Meng, Zhentao Zhang.
       BACKGROUND: TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations.
    AIM OF REVIEW: A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.
    Keywords:  Cancer; Neurodegenerative disease; RNA-binding protein; TATA-box binding protein associated factor 15 (TAF15)
    DOI:  https://doi.org/10.1016/j.jare.2026.04.066
  12. Cell Physiol Biochem. 2026 Apr 06. 60(2): 136-174
    mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.
    Niraj Kumar Jha, Payal Chauhan, Mosleh Mohammad Abomughaid, D Avinash, Abdulmajeed G Almutary, Sorabh Lakhanpal, Ajay Singh, Ghassan M Sulaimani, Hayder M Al-Kuraishy, Hamdoon A Mohammed, Jyotsna Misra, Kunal Thakur, Dhruv Kumar.
      Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.
    Keywords:  mTOR ; Brain ; Neurodegeneration ; Autophagy ; Apoptosis ; Therapeutics
    DOI:  https://doi.org/10.33594/000000858
  13. J Biol Chem. 2026 Apr 27. pii: S0021-9258(26)01958-7. [Epub ahead of print] 113086
    A coherent structural picture of the interaction of Tau with tubulin provides a link to its aggregation.
    Benoît Gigant, Liza Ammar Khodja, Valérie Campanacci, Guy Lippens.
      Tauopathies are a group of neurodegenerative diseases characterized by the presence of insoluble filaments of the Tau protein in the brain. In physiological conditions, Tau is involved in the regulation of microtubule dynamics. The study of its interaction with different tubulin assemblies, using various experimental approaches, leads to a seemingly disparate picture. Here, we propose to integrate this information into a model of how Tau participates in microtubule assembly and stabilization. Related to its intrinsically disordered nature, the binding of Tau to microtubules involves both specific interactions, along protofilaments, and non-specific ones, with the C-terminal region of tubulin subunits. In addition, the recent determination of a Tau:tubulin structure provides a model for a functional dimer of Tau targeting a microtubule aperture between protofilaments. Therefore, Tau regulates microtubule dynamics by modulating both longitudinal and lateral contacts. Finally, we discuss a possible connection of this dimer of Tau with its oligomerization, whether physiological or pathological.
    Keywords:  Alzheimer's disease; Tau protein (Tau); amyloid; microtubule; microtubule dynamics regulation; structural model; tauopathy; tubulin
    DOI:  https://doi.org/10.1016/j.jbc.2026.113086
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