bims-proned 2026-09-06 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–09–06
eighteen papers selected by
Verena Kohler, Umeå University

Targeting of α-Syn Condensate Fluidity by Natural Polyphenols to Retard the Amyloid Transition and Ameliorate α-Syn-Caused Neurotoxicity.
Phase separation in neurodegenerative disorders: a metabolic perspective on protein aggregation and therapeutic targeting.
Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.
Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.
Mechanistic insights on HDAC6 ZnF UBP-Tau interaction through biophysical and computational approaches.
YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.
Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.
Modifications of Lysine Residues 294 and 311 Within the Microtubule-Binding Region Alter Tau Aggregation and Tubulin Binding Equilibria.
Captopril Enables the Inhibition of tRNA-Mediated Tau Aggregation.
Chaperone-assisted selective autophagy (CASA) in polyglutamine-related diseases: From mechanisms to therapeutic perspectives.
Conjugation of Biomolecules to PEG as a Strategy for Efficient Protein Aggregation Inhibition.
Osmolytes suppress liquid‒liquid phase separation and the aggregation of Tau.
Multipathway Aggregation Drives Concentration-Dependent Amyloid Polymorphism and Time-Dependent Morphological Evolution.
Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.
Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.
Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation.
The extracellular Zinc-finger ubiquitin-binding domain of histone Deacetylase 6 enhances podosome formation in neuronal cells.
Therapeutic potential of nasal kisspeptin-54 for reducing α-synuclein accumulation and restoring hippocampal synaptic plasticity in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

J Agric Food Chem. 2026 Aug 26. 74(33): 26183-26195

Targeting of α-Syn Condensate Fluidity by Natural Polyphenols to Retard the Amyloid Transition and Ameliorate α-Syn-Caused Neurotoxicity.

Fengshuo Fan, Bingkuan Xu, Lizhu Zhang, Yuelin Liu, Zhenchao Li, Yinghui Liu, Ruyue He, Lingjun Zheng, Haijia Yu.

  The key pathology of Parkinson's disease (PD) is the presence of Lewy bodies, which contain aggregated α-synuclein (α-Syn). Recent studies revealed that liquid-liquid phase separation (LLPS) is critical for α-Syn aggregation. This study investigates the regulatory effects of three food-related natural polyphenols on α-Syn LLPS and amyloid transition. We discovered that, rather than epigallocatechin gallate (EGCG) and gallic acid (GA), tannic acid (TA) dynamically regulates α-Syn LLPS by increasing α-Syn mobility within the condensates. TA promotes α-Syn condensate fusion but retards the liquid-to-solid phase transition, inhibiting α-Syn aggregation. Further studies showed that TA strongly blocks α-Syn seed-induced aggregation in neuronal cells and exerts neuroprotective effects against α-Syn in Caenorhabditis elegans. Our findings demonstrate that the regulation of LLPS-driven α-Syn amyloid aggregation by small molecules differs from that of nucleation-dependent deposition, providing new insights into targeting α-Syn phase separation in the treatment of PD and other protein aggregation-related diseases.

Keywords:  Parkinson’s disease (PD); amyloid aggregation; phase separation; polyphenol; α-synuclein

DOI:  https://doi.org/10.1021/acs.jafc.5c17436
Transl Neurodegener. 2026 Aug 31. pii: 43. [Epub ahead of print]15(1):

Phase separation in neurodegenerative disorders: a metabolic perspective on protein aggregation and therapeutic targeting.

Shujun Peng, Hui Chen, Guowei Yin, Alexei Verkhratsky, Chenju Yi.

  Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are increasingly recognised as dynamic organisers of intracellular biochemistry, particularly in neurons where spatially restricted signalling, RNA metabolism, and proteostasis are essential. Aberrant phase transitions of disease-associated proteins, including TDP-43, FUS, tau, and α-synuclein, contribute to protein aggregation and neurodegenerative pathology. Beyond protein-intrinsic sequence features, metabolic state has emerged as an important contextual regulator of condensate assembly, material properties, and liquid-to-solid maturation. Metabolic cues, including ATP availability, NAD+/NADH balance, redox state, lipid composition, enzyme-mediated post-translational modifications, and cellular stress responses, can influence the phase behaviour across biochemical, cellular, and disease-model systems. However, direct causal evidence in neurons, animal models, and human neurodegenerative diseases remains uneven and protein-specific. Here, we review LLPS in neurodegenerative disorders from the metabolic perspective, distinguishing established mechanisms from plausible but incompletely validated links. We discuss how pathological condensates may impair RNA metabolism, synaptic function, proteostasis, and cognition, and critically evaluate emerging therapeutic strategies that aim to modulate aberrant phase behaviour. This review therefore provides a cautious framework in which metabolic dysregulation is considered a potential upstream contributor to pathological phase transitions rather than an established master regulator.

Keywords:  Cognition; Metabolic enzymes; Neurodegenerative diseases; Pathological protein aggregation; Phase separation

DOI:  https://doi.org/10.1186/s40035-026-00575-z
Biochemistry. 2026 Aug 27.

Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.

Md Nadir Hassan, Murtaza Hussain, Faisal Nabi, Devendra Singh, Sumbul Yasmeen, Md Sharique Zafar, Irum Rizvi, Syed Mohammad Zakariya, Waseem A Siddiqui, Vladimir N Uversky, Rizwan Hasan Khan.

Parkinson's disease (PD) is characterized by the pathological aggregation of α-synuclein (α-syn) into β-sheet-rich fibrils, contributing to neuronal toxicity and oxidative stress. In this study, we investigated the inhibitory and disaggregating effects of Triprolidine (TC) on α-syn fibrillation through a combined experimental and computational approach. Biophysical assays, including ThT assay, DLS, and ANS assays, demonstrated that TC inhibits α-syn fibrillation in a concentration-dependent manner (IC50 ≈ 255 μM), disrupts preformed fibrils, and maintains the protein's native form. CD data further revealed that TC prevents the transition of α-syn to its toxic β-sheet-rich form and facilitates partial structural reversal during disaggregation. To elucidate the molecular mechanism of inhibition, we performed all-atom molecular dynamics (MD) simulations followed by Markov State Model (MSM) construction. The simulations revealed that TC binding remodels the conformational landscape of α-syn by stabilizing compact, disordered states and reducing the population of β-sheet-prone intermediates, particularly in the aggregation-prone NAC region. MSM analysis identified metastable states with diminished aggregation potential and reduced inter-residue contact probability, offering mechanistic insights into how TC interferes with early nucleation events. TC attenuates seeded fibrillation in a concentration-dependent manner too. Complementary cellular assays, including MTT and hemolytic assays, confirmed a significant reduction in α-syn-induced cytotoxicity upon TC treatment, with a decrease in ROS levels as confirmed by the DCFH-DA assay. Together, these findings demonstrate that TC modulates both the structural dynamics and functional toxicity of α-synuclein, and highlight its potential as a promising chemical modulator for further investigation in PD-related protein aggregation.

DOI: https://doi.org/10.1021/acs.biochem.6c00571
ACS Chem Neurosci. 2026 Sep 02. 17(17): 3156-3168

Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.

Min-Kyung Nam, Yeram Oh, Yemi Choi, Jieun Lee, Gi Heon Jeong, Sangjun Park, Seung-Ah Yoo, Moonseok Kim, Seongman Kang, Hyangshuk Rhim.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.

Keywords:  Amyotrophic lateral sclerosis; NABi; SOD1G93A; aggregation inhibitor; neurodegenerative diseases; protein aggregation; therapeutic peptide; β-sheet inhibitor

DOI:  https://doi.org/10.1021/acschemneuro.5c00977
Methods Enzymol. 2026 ;pii: S0076-6879(26)00251-X. [Epub ahead of print]734 79-103

Mechanistic insights on HDAC6 ZnF UBP-Tau interaction through biophysical and computational approaches.

Abhishek Ankur Balmik, Shweta Kishor Sonawane, Nalini Vijay Gorantla, Subashchandrabose Chinnathambi.

  Histone deacetylase 6 is a unique cytoplasmic deacetylase implicated in cellular functions such as microtubule dynamics, protein quality control, ubiquitin-mediated degradation and neurodegenerative disorders. The ZnF UBP (zinc finger ubiquitin binding protein) domain of HDAC6 is known to be directly modulate several cellular processes linked to neurodegeneration such as sequestering polyubiquitinated aggregates and regulating protein aggregate clearance mechanisms in neurons. Microtubule associated protein Tau (MAP Tau) undergoes aggregation in neurodegenerative conditions like Alzheimer's disease (AD) and several other tauopathies. Tau is a natively disordered protein which is functionally regulated by wide array of post-translational modifications (PTMs) as well as by interacting with several proteins. This methodological study aims to understand the molecular interaction between HDAC6 ZnF UBP domain and Tau protein in order to elucidate the role of HDAC6 ZnF UBP domain in Tau aggregation and stability. We employed an integrated biochemical, biophysical and computational workflow to characterize the interaction between HDAC6 ZnF UBP and Tau. NMR spectroscopy, isothermal titration calorimetry and pull-down assay with purified HDAC6 ZnF UBP and Tau proteins demonstrated direct interaction between the two, with interaction associated structural perturbations and favourable binding kinetics as observed in NMR and ITC respectively. Computational analyses further suggest the formation of Tau-HDAC6 ZnF UBP complex and provided underlying molecular interactions involved in the binding of these two proteins. The findings in this study helps to advance the current understanding of regulatory role of HDAC6 specifically in Tau biology and further provides a useful framework for investigating the modulation of aggregation prone proteins via protein-protein interaction in neurodegenerative diseases.

Keywords:  Alzheimer disease; HDAC6; NMR; Protein aggregation; Protein-protein interaction; Tau protein; ZnF UBP

DOI:  https://doi.org/10.1016/bs.mie.2026.07.009
Nat Commun. 2026 08 21. pii: 9357. [Epub ahead of print]17(1):

YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.

Kang Ren, Mingjie Cheng, Qiudan Luo, Boxin Zhang, Haosheng Zhang, Zhe Li, Yuxin Liu, Yujie Wang, Ting Kang, Xiaoming Dai, Jiong Chen, Yuanming Cheng, Liangqian Huang.

Proteostasis failure drives multiple neurodegenerative disorders (NDs), and ATP-independent chaperone pathways that support neuronal proteostasis remain poorly defined. Here, we identify the N6-methyladenosine (m6A)-binding protein YTHDC1 as an ATP-independent molecular chaperone, whose activity is mediated by a highly acidic polyaspartate/glutamate (polyD/E) segment. YTHDC1 prevents protein misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Deletion of the polyD/E segment abolishes these activities, whereas aromatic-cage mutants retain chaperone activity, demonstrating independence from m6A recognition. We identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein hnRNPA1 as a YTHDC1 client. YTHDC1 maintains liquid-like hnRNPA1 condensates, delays fibrillization of disease-associated mutants, and limits stress-granule sequestration, while mitigating mutant hnRNPA1-induced neurite growth defects in primary neurons. These findings define a proteostatic function of YTHDC1 and highlight its chaperone activity as a potential target for mitigating protein aggregation in ALS-related NDs.

DOI: https://doi.org/10.1038/s41467-026-77016-y
Neuromolecular Med. 2026 Aug 31. pii: 51. [Epub ahead of print]28(1):

Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.

Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad, Tehreem Mushtaq, Mahtab Ahmad Khan, Anam Hameed.

  Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.

Keywords:  Autophagy; Extracellular Propagation; Lysosomal Dysfunction; Nanoparticles; Parkinson’s Disease; α-Synuclein

DOI:  https://doi.org/10.1007/s12017-026-08948-3
Angew Chem Int Ed Engl. 2026 Sep 03. e1521091

Modifications of Lysine Residues 294 and 311 Within the Microtubule-Binding Region Alter Tau Aggregation and Tubulin Binding Equilibria.

Dominik P Vogl, Mario Migotti, Robert Konrat, Anne C Conibear, Christian F W Becker.

  Dysfunction of the microtubule-associated protein Tau is a central feature of Alzheimer's disease and related tauopathies, yet how site-specific lysine modifications modulate the functional and pathological states of Tau remains poorly understood. Here, we combine protein semi-synthesis with segmental isotope labelling and NMR spectroscopy of full-length Tau, to dissect how lysine acetylation and carboxymethylation within the microtubule-binding region of Tau regulate its interactions with tubulin, microtubules, and amyloid assembly. Site-specific modification at lysine 294 delays Tau-mediated tubulin polymerization and fibril formation, whereas acetylation at lysine 311 exerts more moderate effects, but alters fibril morphology. NMR spectroscopy of segmentally isotope-labelled Tau variants indicates that single lysine acetylation does not measurably weaken Tau binding to pre-formed microtubules; however, bivalent acetylation reduces microtubule binding, possibly by cumulative charge neutralization. Together, these results indicate that lysine acetylation redistributes Tau between functional states in a site- and valency-dependent manner. Our study helps to establish a mechanistic framework linking combinatorial lysine modifications to Tau dysfunction and highlights the utility of region-resolved structural approaches to decipher posttranslational modification-dependent equilibria in intrinsically disordered proteins.

Keywords:  Microtubule assembly; Posttranslational modifications; Protein semi‐synthesis; Tau protein; segmental isotope labeling

DOI:  https://doi.org/10.1002/anie.1521091
Langmuir. 2026 Sep 01. 42(34): 24939-24945

Captopril Enables the Inhibition of tRNA-Mediated Tau Aggregation.

Boru Peng, Quan Deng, Xiaohua Zhu, Youyu Zhang.

Tau is an intrinsically disordered protein critical to the nervous system, and its aberrant aggregation is a key pathogenic factor in multiple diseases. However, the underlying triggers remain elusive. Here, using in vitro reconstitution and high-resolution imaging, we identify tRNA as a major inducer of tau aberrant aggregation. Mechanistically, tRNA drives the formation of fibrillar aggregates from tau liquid-liquid phase separation (LLPS) condensates via electrostatic interactions, which over time can evolve into pathological aggregates. Moreover, captopril (CAP) effectively inhibits both general and tRNA-induced tau aggregation, positioning CAP as a potential therapeutic candidate. This work offers an avenue for treating aberrant phase separation-induced tau aggregation using small-molecule compounds.

DOI: https://doi.org/10.1021/acs.langmuir.6c02865
J Huntingtons Dis. 2026 Sep 03. 18796397261478173

Chaperone-assisted selective autophagy (CASA) in polyglutamine-related diseases: From mechanisms to therapeutic perspectives.

Barbara Tedesco, Marta Chierichetti, Riccardo Cristofani, Angelo Poletti.

  Chaperone-assisted selective autophagy (CASA) is a crucial process aimed at maintaining proteostasis in several neurodegenerative diseases associated with protein misfolding, including polyglutamine (polyQ) diseases. Autophagy is a critical lysosome-mediated degradation pathway, particularly essential in neurons, which are highly susceptible to proteotoxic stress due to their post-mitotic nature. Selective autophagy pathways, including CASA, ensure the targeted removal of misfolded proteins and damaged organelles, thereby preserving cellular homeostasis. CASA is based on the intersection of chaperones and autophagy, where HSPB8 and BAG3 interact with HSPA and STUB1 forming a complex that identifies, ubiquitinates, and directs aberrant proteins toward autophagosomes for subsequent lysosomal degradation. In polyQ diseases, such as spinal and bul muscular atrophy (SBMA) and Huntington's disease (HD), mutant proteins accumulate, overwhelming the protein quality control systems. The CASA components are upregulated as a compensatory response, promoting toxic aggregates clearance and cellular damage mitigation. However, chronic proteotoxic stress and progressive impairment of autophagic and lysosomal pathways eventually limit CASA efficiency, contributing to disease progression. The review highlights how CASA exerts its protective activities in polyQ diseases and reports therapeutic strategies aimed at enhancing CASA activity, including pharmacological inducers and combinatorial approaches targeting autophagy and the ubiquitin-proteasome system. Overall, CASA emerges as a crucial adaptive mechanism and a promising therapeutic target in polyQ-related neurodegeneration.

Keywords:  CAG repeat expansions; Huntington disease; chaperone-assisted selective autophagy; polyglutamine diseases; protein misfolding; spinal and bul muscular atrophy

DOI:  https://doi.org/10.1177/18796397261478173
ACS Appl Bio Mater. 2026 Sep 01.

Conjugation of Biomolecules to PEG as a Strategy for Efficient Protein Aggregation Inhibition.

Nidhi Anilkumar Jamuna, Merlin Thomas, Dharini Arumugam, Sarthak Mandal.

  Neurodegenerative diseases are a group of progressive disorders characterized by the degeneration of neurons with significant cognitive decline and motor and autonomic dysfunction. They are linked to protein aggregation that leads to cellular toxicity, neuronal death, and brain atrophy due to the accumulation of amyloid plaques and tau tangles in the brain. Recent advances in biomaterials have introduced several biocompatible polymers and conjugated biomolecules as potential inhibitors for protein aggregation. Conjugation to biocompatible polyethylene glycol (PEG) is the most widely used strategy for enhancing bioavailability, biocompatibility, and pharmacokinetic properties of small molecular drugs. In this work, we have designed and synthesized two biomolecule-polymer conjugates, namely, Tre-CA-mPEG and LA-CA-mPEG, by combining a biocompatible, nontoxic polymer monomethoxy PEG (mPEG), a steroid bile acid, cholic acid (CA), and a functional biomolecule, trehalose (Tre) or lipoic acid (LA). These building blocks have significant protein stabilization and neuroprotective attributes, which are important for protein aggregation inhibition. The size distributions of the self-assemblies formed by the Tre-CA-mPEG and LA-CA-mPEG bioconjugates were determined by dynamic light scattering (DLS) measurements. Both the PEGylated bioconjugate assemblies show promising results for inhibition of protein aggregation. The hydrophobic interactions provided predominantly by the steroidal core moiety, together with hydrogen bonding interactions within the PEG corona of the self-assemblies, play a crucial role in protein stabilization and fibrillation inhibition. LA-CA-mPEG bioconjugate exhibits superior effects in delaying aggregation kinetics and enhancing the inhibition of protein aggregation compared to the Tre-CA-mPEG bioconjugate. This enhanced protein fibrillation inhibition can be attributed to the larger hydrophobic surface and stronger interactions arising from the LA-CA-mPEG nanoassemblies.

Keywords:  Alzheimer’s disease; amyloid aggregation; biomolecule-polymer conjugates; fibrillation inhibition; neurodegenerative diseases; protein stabilization

DOI:  https://doi.org/10.1021/acsabm.6c00990
Biochimie. 2026 Sep 01. pii: S0300-9084(26)00207-5. [Epub ahead of print]

Osmolytes suppress liquid‒liquid phase separation and the aggregation of Tau.

Jingye Lin, Zongbao Wang, Chenxi Liu, Yiwen Hua, Sen Li.

  Tau liquid-liquid phase separation (LLPS) is increasingly recognized as an early event that promotes pathological aggregation in Alzheimer's disease and other tauopathies. Osmolytes are natural chemical chaperones that stabilize protein conformations, yet their effects on Tau phase behavior remain poorly understood. Here, we show that sucrose, trehalose, glucose, maltose, and betaine suppress Tau LLPS and dissolve preformed Tau droplets, shifting the equilibrium toward soluble monomers in vitro. Among the five osmolytes, trehalose and glucose exhibited the strongest inhibitory effects on Tau LLPS. They also suppressed the liquid-to-solid phase transition of Tau droplets, as evidenced by reduced Thioflavin T (ThT) fluorescence, inhibition of fibril formation observed by transmission electron microscopy (TEM), and improved condensate dynamics in fluorescence recovery after photobleaching (FRAP) assays performed in okadaic acid-treated cells. These results indicate that osmolytes interfere with multiple stages of Tau phase transition-from initial condensate formation to pathological maturation and fibrillization. Our findings establish osmolytes as effective modulators of Tau phase behavior and provide mechanistic insights into the physicochemical regulation of Tau phase transitions.

Keywords:  Alzheimer's disease; Liquid‒liquid phase separation; Osmolytes; Protein stability; Tau protein aggregation

DOI:  https://doi.org/10.1016/j.biochi.2026.08.019
J Phys Chem Lett. 2026 Aug 27. 17(34): 9786-9796

Multipathway Aggregation Drives Concentration-Dependent Amyloid Polymorphism and Time-Dependent Morphological Evolution.

Kamal Bhandari, Wuzhou Xiong, Tianyi Hou, Pu Chun Ke, Feng Ding.

Amyloid aggregation into polymorphic fibrils is central to many neurodegenerative and systemic diseases, yet the physical origins of fibril polymorphism and time-dependent morphological evolution remain unclear. Because mature fibril morphologies are separated by high energy barriers, direct interconversion is unlikely. Here, we propose a multipathway aggregation model in which oligomeric nuclei with distinct sizes and chemical potentials seed different fibril morphologies. The abundance and temporal evolution of these polymorphs are governed by pathway-specific fibrillization barriers and fibril stabilities, allowing kinetically favored morphologies to dominate early but to be replaced by more stable forms over time. Differences in nucleus size further introduce concentration dependence, biasing aggregation toward different intermediates and fibril morphologies at low versus high concentrations. This framework helps rationalize the substantial concentration disparity between in vitro experiments and in vivo environments and highlights the importance of considering multipathway, concentration-dependent aggregation in studying amyloidosis and designing antiamyloidosis strategies.

DOI: https://doi.org/10.1021/acs.jpclett.6c01930
Methods Enzymol. 2026 ;pii: S0076-6879(26)00172-2. [Epub ahead of print]734 1-28

Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.

Marisel Sanchez, Jeff Kuret.

  Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.

Keywords:  Alzheimer’s disease; Lysine methylation; Mass spectrometry; Post-translational modification; Protein aggregation; Reductive methylation; Tau protein; Tauopathies

DOI:  https://doi.org/10.1016/bs.mie.2026.05.044
J Phys Chem B. 2026 Sep 03. 130(35): 8770-8781

Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.

Meenal Jain, Silvina Matysiak.

Dysregulated calcium homeostasis is a hallmark of neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. In Alzheimer's disease (AD), the aggregation of amyloid beta (Aβ) peptides at neuronal membranes is shown to be modulated by the presence of Ca2+ ions, yet the molecular mechanism by which Ca2+ reshapes Aβ aggregation at anionic membrane surfaces remains poorly understood. To address this knowledge gap, we employed coarse-grained molecular dynamics simulations to investigate the aggregation of the model amyloidogenic K16LVFFAE22 fragment of Aβ (Aβ16-22), on a mixed bilayer composed of 30% anionic phosphatidylserine (PS) and 70% zwitterionic phosphatidylcholine (PC) (30% POPS, 70% POPC) in the presence of Ca2+ ions. We find that Ca2+ ions screen the surface charge and reduce hydrophobic packing defects at the membrane surface. Since peptide binding is primarily driven by electrostatic interactions between positively charged residues and anionic lipids, followed by hydrophobic interactions, these Ca2+-induced changes delay peptide adsorption onto the bilayer, promoting the formation of larger aggregates in solution that subsequently adsorb as preformed aggregates. This is in contrast with the no-Ca2+ condition, where peptides bind earlier as small oligomers and aggregate on the bilayer. Following adsorption, PS-Ca2+-PS ionic bridges rapidly condense PS lipids around peptide aggregates and reduce their lateral mobility. This leads to larger, less ordered aggregates with shallower insertion and hydrophobic residues exposed to the solution, a structural feature associated with seeding-active aggregates. These findings align with Western blot analyses showing enhanced Aβ aggregation with Ca2+ ions and provide a molecular basis for the observed aggregation behavior. Together, our results provide mechanistic insight into how calcium alters the membrane-mediated aggregation pathway of amyloidogenic peptides, potentially informing therapeutic strategies against amyloid pathology.

DOI: https://doi.org/10.1021/acs.jpcb.6c02606
ACS Chem Neurosci. 2026 Sep 02. 17(17): 3150-3155

Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation.

Renan C Ratis, Juliana S Bonini, Angelica B W Bold.

  Extracellular protein aggregates have long been viewed primarily as toxic deposits, yet this framing fails to explain a critical clinical observation: removal of amyloid-β oligomers does not halt or reverse Alzheimer's disease progression. Here, we propose that this paradox reflects the emergence of a self-sustaining intracellular signaling state, initiated by aggregate-driven receptor clustering but capable of persisting independently of the original extracellular trigger. We argue that oligomeric assemblies act as multivalent scaffolds that cross-link cell-surface receptors, inducing nanoscale clustering and the formation of signaling-competent membrane platforms. In Alzheimer's disease, this mechanism links amyloid-β to a receptor complex involving PrPc and mGluR5, leading to Fyn activation and downstream tau hyperphosphorylation. Critically, redistributed tau enhances Fyn recruitment to postsynaptic compartments, establishing a positive feedback loop in which kinase activity and tau pathology become mutually reinforcing, and progressively decoupled from the initiating amyloid signal. This self-amplifying circuit provides a mechanistic basis for the limited efficacy of amyloid-targeted therapies and reframes the therapeutic window problem in neurodegeneration. Beyond Alzheimer's disease, we propose that clustering-driven feedback loops may represent a generalizable principle in proteinopathies involving extracellular or membrane-associated aggregates─such as α-synuclein─though the applicability of this principle appears to depend on whether the aggregating protein directly engages cell-surface receptor systems. This framework shifts the focus from aggregate burden to membrane organization and feedback topology as determinants of disease progression, and identifies the tau-Fyn feedback loop as a candidate therapeutic target in proteinopathies.

Keywords:  beta-amyloid; lipid raft; neurons; positive feedback; proteinopathy

DOI:  https://doi.org/10.1021/acschemneuro.6c00331
Methods Enzymol. 2026 ;pii: S0076-6879(26)00188-6. [Epub ahead of print]734 301-326

The extracellular Zinc-finger ubiquitin-binding domain of histone Deacetylase 6 enhances podosome formation in neuronal cells.

Tazeen Qureshi, Abhishek Ankur Balmik, Subashchandrabose Chinnathambi.

  Neurodegenerative disorders are characterized by progressive synaptic failure, neuronal loss, and the accumulation of pathological protein aggregates. A critical but often overlooked driver of this decline is cytoskeletal dysregulation, which compromises essential cellular functions ranging from intracellular transport to morphological stability. Histone Deacetylase 6 (HDAC6) is a central regulator of these dynamics, yet its role in neurodegeneration remains controversial: while its deacetylase activity is often linked to microtubule instability and toxicity, its ubiquitin-binding functions are essential for aggregate clearance. We have previously demonstrated that the ZnF-UBP domain acts as a direct modulator of cytoskeletal architecture, enhancing the formation of actin-rich migratory structures-such as podosomes and lamellipodia-and promoting neuritic outgrowth. It does this by inducing increased localization of actin remodelling proteins to the podosomes, ultimately conferring enhanced migration potential to cells. This chapter highlights the protocols essential for understanding the therapeutic potential of the HDAC6 Zinc Finger Ubiquitin-Binding Protein (ZnF-UBP) domain, in the context of actin remodelling through podosome structures.

Keywords:  Alzheimers disease; Cytoskeleton; Histone deacetylase 6; Podosomes; Tau; Zinc-finger ubiquitin-binding domain (ZnF UBP)

DOI:  https://doi.org/10.1016/bs.mie.2026.05.060
Turk J Med Sci. 2026 ;56(4): 1320-1331

Therapeutic potential of nasal kisspeptin-54 for reducing α-synuclein accumulation and restoring hippocampal synaptic plasticity in a 6-hydroxydopamine-induced rat model of Parkinson's disease.

Ayşegül Gemici Sinen, Emre Savran, Okyanus Bora Güleç, Osman Sinen, Narin Derin.

   Background/aim: Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons and pathological aggregation of α-synuclein (α-syn), leading to significant motor and cognitive impairments. Kisspeptin-54 (KP-54), a neuropeptide primarily involved in reproductive regulation, has recently been implicated in neurorestorative processes, with emerging evidence suggesting beneficial effects on locomotor activity and cognitive function. However, its therapeutic potential in PD has not yet been fully investigated. This study aimed to evaluate the therapeutic efficacy of chronic nasal KP-54 administration in a 6-hydroxydopamine (6-OHDA) rat model of PD, focusing on motor and cognitive outcomes, hippocampal synaptic plasticity, and α-syn pathology.
Materials and methods: Adult Sprague-Dawley rats underwent unilateral 6-OHDA injections into the medial forebrain bundle to induce dopaminergic degeneration. Beginning 3 weeks after lesion induction, animals received daily nasal KP-54 or vehicle treatment for an additional 3 weeks. Motor performance was assessed using the catalepsy, beam balance, and open field tests, whereas cognitive function was evaluated using the Y-maze and object location test. Baseline assessments were conducted on day 0 prior to lesion formation. Electrophysiological recordings obtained from the hippocampal CA1 region were used to assess synaptic plasticity. Dopaminergic neuron survival and α-syn accumulation in the substantia nigra and hippocampus were quantified by immunofluorescence analysis.
Results: Chronic nasal KP-54 significantly ameliorated motor and cognitive deficits induced by 6-OHDA. KP-54 restored hippocampal synaptic plasticity, enhanced the survival of tyrosine hydroxylase-positive dopaminergic neurons, and reduced α-syn accumulation in both the substantia nigra and hippocampus.
Conclusion: The findings indicate that nasal KP-54 administration exerts neurorestorative effects in a 6-OHDA rat model of PD by preserving dopaminergic neurons, improving synaptic function, and attenuating pathological α-syn aggregation. These results position KP-54 as a promising candidate for disease-modifying therapy in Parkinson's disease.

Keywords:  Parkinson’s disease; hippocampus; kisspeptin-54; synaptic plasticity; α-synuclein

DOI:  https://doi.org/10.55730/1300-0144.6376