bims-proned 2025-11-23 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–11–23
eighteen papers selected by
Verena Kohler, Umeå University

DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.
Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.
Binding domains of α-synuclein receptors with monomeric/oligomeric α-synuclein: Implications for Parkinson's disease.
Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy.
L-arginine interferes with functional studies of amyloid proteins.
Coordination of Anle138b to Silver Results in Selective Reduction of a C-terminal truncated Alpha-synuclein Protein and Increased Aggregate Size.
The Ubiquitin-Proteasome System in Brain Disorders: Pathogenic Pathways, Post-Translational Tweaks, and Therapeutic Frontiers.
Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases.
Kinetic Mechanism of Substoichiometric Inhibition of Huntingtin Exon-1 Protein Aggregation by Selenium Nanoparticles.
Synuclein Proteoforms: Role in Health and Disease.
Controlling interfacial protein adsorption, desorption and aggregation in biomolecular condensates.
Native PEG-PLGA Attenuates β-Amyloid Aggregation and Toxicity under In Vitro Conditions.
The role of RNA in the nanoscale organization of α-synuclein phase separation.
LRRK2 Degraders for Parkinson's Disease and Inflammation: Tau and α‑Synuclein Degraders for Neurodegeneration.
Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration.
In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.
Morphological and Hyperphosphorylation Transitions of Nanoscale Tau Aggregates in Alzheimer's Disease.
Discrimination of Formation Processes of Amyloid β Fibrils with Distinct Morphologies Using Rheo-NMR Spectroscopy.

bioRxiv. 2025 Oct 02. pii: 2025.10.02.680111. [Epub ahead of print]

DnaJB1 chaperone inhibits tau aggregation by recognizing its N-terminus.

Pawel M Wydorski, Paulina Macierzynska, Sofia Bali, Jaime Vaquer-Alicea, Lukasz A Joachimiak.

A network of protein folding and degradation machineries maintains protein homeostasis by preventing the accumulation of misfolded proteins and by facilitating their clearance. These systems are also crucial for the inhibition of protein aggregation in neurodegenerative diseases where misfolded proteins often aggregate into β-rich amyloid fibrils. How these machineries selectively recognize pathological aggregates over normal conformations remains unclear. Here, we present the molecular logic for how a Hsp70 co-chaperone from the J-domain protein family, DnaJB1, binds pathological aggregates of the microtubule-associated protein tau through the recognition of the flexible N-terminus that comprises the disordered fuzzy coat of fibrils. We show that this interaction contributes to the regulation of tau assembly in cellular models of tau aggregation and depends on the presence of the negatively charged residues. We determined that DnaJB1 inhibits tau aggregation in vitro through these interactions, and found that this weak, transient binding can be enhanced by the presence of polyanionic factors such as heparin. As prospective client-binding sites, we identified the charged hinge between the two β-sandwich C-terminal domains I and II, as well as the conserved J-domain of this chaperone. This work presents novel biochemical and structural insights into how the molecular chaperone DnaJB1 recognizes full-length forms of tau protein in a pathological context.

DOI: https://doi.org/10.1101/2025.10.02.680111
Adv Sci (Weinh). 2025 Nov 20. e05228

Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.

Rūta Sniečkutė, Darius Šulskis, Arūnė Jocytė, Urtė Venclovaitė, Rimgailė Tamulytė, Mantas Žiaunys, Vytautas Smirnovas, Andrius Sakalauskas.

  α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such as Parkinson's disease (PD) or Multiple System Atrophy (MSA). Misfolded aSyn, which primarily originates in the cell cytosol, transmits between neurons, promoting a prion-like propagation. However, extracellular environments such as interstitial and cerebrospinal fluids (ISF & CSF) play a major role in its clearance and pathological transformation. The molecular components of CSF, including proteins, glycosaminoglycans, and metal ions, may influence the aggregate morphology, structure, and cytotoxicity to cells. To better understand how extracellular composition affects aggregates and their formation, artificial cerebrospinal fluid (aCSF) is employed to mimic potential aggregation processes occurring in CSF. Distinct aSyn fibrils are observed that exhibited low stability outside aCSF, and the removal of key CSF components led to its structural alterations. Cryo-electron microscopy revealed that these fibrils possess an electron density pocket coordinated with polar basic AAs (K43, K45, H50) that is also observed in aggregates obtained from PD and MSA patients. The findings illustrate the importance of physiologically relevant conditions in studying aSyn aggregation and may explain why disease-related fibril structure replication in vitro has not yet been successful.

Keywords:  Cryo‐EM; Parkinson's disease; aggregate structure analysis; alpha‐synuclein aggregation; physiological conditions

DOI:  https://doi.org/10.1002/advs.202505228
Biomed Pharmacother. 2025 Nov 20. pii: S0753-3322(25)00996-5. [Epub ahead of print]193 118802

Binding domains of α-synuclein receptors with monomeric/oligomeric α-synuclein: Implications for Parkinson's disease.

Rosalie Elvira, Jia Sheng Guan, Yuguang Mu, Eng-King Tan, Zhi Dong Zhou.

  Parkinson's disease (PD) and related synucleinopathies are characterized by the pathological aggregation and spread of alpha-synuclein (α-syn), a protein central to neurodegeneration. Currently three neuronal receptors -Family with sequence similarity 171 member A2 (FAM171A2), Lymphocyte Activation Gene 3 (LAG3), and Amyloid-Precursor-Like Protein 1 (APLP1) have been identified as critical mediators of α-syn preformed fibril (PFF) uptake, propagation, and neurotoxicity. Here we utilize AlphaFold 3 program to predict binding domains of respective α-syn receptors with monomer and oliogmer α-syn proteins. Our prediction outcomes show that FAM171A2 protein exhibits a credible interaction interface with α-syn monomer. Whereas AlphaFold3 failed to predict stable complex formation between FAM171A2 and oligomeric α-syn protein. The APLP1 was predicted to interact with both monomeric and hexameric α-syn proteins. However, LAG3 failed to produce a high-confidence binding model with either monomeric or oligomeric α-syn. Neither full-length nor domain-restricted constructs resulted in accurate prediction of the experimentally identified interaction between LAG3 and α-syn protein. Our findings suggest that FAM171A2 may serve as a selective receptor for early-stage α-syn protein transmission. Although there is a lack of no direct interactions between LAG3 and monomeric or oligomeric α-syn, APLP1 may act as an adaptor protein for LAG3 protein to facilitate binding of LAG3 receptor with α-syn proteins. We discuss the pathophysiologic implications of the different binding affinity/domains of α-syn receptors with monomeric/oligomeric α-syn in PD.

Keywords:  APLP1; Endocytosis; FAM171A2; LAG3; Membrane receptors; Parkinson Disease; Preformed fibril (PFF); Protein aggregation; Synucleinopathies; α-synuclein

DOI:  https://doi.org/10.1016/j.biopha.2025.118802
Life Sci Alliance. 2026 Feb;pii: e202503393. [Epub ahead of print]9(2):

Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy.

Chatrawee D Shepard, Xinmin Chang, Paul M Seidler, Sean P Curran.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease hallmarked by the presence of amyloid-β (Aβ) plaques and tau fibrils but with limited treatment options. Here, we describe two plant-derived natural products with distinct mechanisms of action on tau fibril disaggregation and prionogenic seeding. We first characterized the effects of oolonghomobisflavan A (OFA) and oolonghomobisflavan B (OFB) treatments, which alter the transcriptional landscape toward enhanced proteostasis and reverse the shortened lifespan in a Caenorhabditis elegans model expressing pathogenic human tau ("hTau-expressing"), but increase healthspan. Mechanistically, OFA treatment reduced the burden of tau protein aggregation and promoted tau disaggregation in hTau-expressing C. elegans and also inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer's disease brain donors. We leveraged this finding to develop a facile screening approach for compounds, like OFA, that could mitigate tau aggregation, which revealed plumbagin (PB) as a potent inhibitor of tau monomer aggregation which is mechanistically distinct from the tau fibril disaggregase activity associated with OFA. Collectively, this study reveals a new strategy for identifying therapeutic compounds that target tauopathy and provides mechanistic insight supporting the neuroprotective effects of plant-derived natural products.

DOI: https://doi.org/10.26508/lsa.202503393
Protein Expr Purif. 2025 Nov 14. pii: S1046-5928(25)00196-2. [Epub ahead of print]239 106854

L-arginine interferes with functional studies of amyloid proteins.

H P Chethana, U Rathan Kumar, Gunimala Chakraborty, Arshdeep Sidhu.

  Intrinsically disordered proteins/regions are abundant in cancer signalling pathways and neurodegenerative diseases like Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, etc. Purification of intrinsically disordered proteins can be challenging due to their sticky nature. For intrinsically disordered amyloid proteins, in-vitro aggregation studies are ideal experiments to study their liquid to solid transition. However, over-expression of these proteins in E. coli often results in insoluble protein fraction that ends up in cell-pellet as inclusion bodies, on lysis and centrifugation. Supplementing purification buffers with l-arginine is known to increase the solubility of proteins. For most of the structured proteins increasing solubility translates into a higher yield of functional proteins. However, for aggregation prone proteins associated with neurodegenerative diseases, like α-synuclein (Parkinson's disease), Aβ (Alzheimer's disease), fused in sarcoma (amyotrophic lateral sclerosis), etc. inclusion of l-arginine might interfere with aggregation studies. To test our hypothesis, we purified aggregation prone α-synuclein and fused in sarcoma protein in the presence and absence of l-arginine and studied their fibrillization. While recombinant FUS is difficult to prepare, purification of α-synuclein is well established but in all the protocols a significant amount of protein remains as insoluble fraction in the pellet. Inclusion of l-arginine increases the yield of protein purification by about 3 folds for both the proteins, but the resulting protein does not aggregate into fibrils thus showing that increased solubility of amyloid proteins (α-synuclein and fused in sarcoma) in the presence of l-arginine is not suitable for aggregation studies.

Keywords:  Amyloids; Fused in sarcoma; Neurodegenerative diseases; Solubility; l-Arginine; α-synuclein

DOI:  https://doi.org/10.1016/j.pep.2025.106854
bioRxiv. 2025 Oct 03. pii: 2025.10.01.679869. [Epub ahead of print]

Coordination of Anle138b to Silver Results in Selective Reduction of a C-terminal truncated Alpha-synuclein Protein and Increased Aggregate Size.

Kelly L Rue, Susana Herrera, Zhi-Chun Shi, Indranil Chakraborty, Jeremy Tachiki, Josue Ballesteros, Julie K Andersen, Gordon J Lithgow, Wisam A Al Isawi, Gellert Mezei, Minna Yakov Schmidt, Raphael G Raptis.

Parkinson's disease (PD) is a prevalent age-related neurodegenerative syndrome, partially thought to be caused by a decrease in alpha-synuclein proteostasis. Anle138b = 5-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-1H-pyrazole ( HL ), is undergoing clinical trials as a promising mitigator of alpha-synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: H 2 L(ClO 4 ) , [CuI(μ-L)] 3 , and [AgI(μ-L)] 3 . To better understand the bioviability of these compounds, we monitored their effects in a cell culture model of alpha-synuclein protein aggregation using human alpha-synuclein pre-formed fibrils (PFFs). Using two different anti-alpha-synuclein antibodies, our data suggests that [AgI(μ-L)] 3 decreases a C-terminal truncated protein that is approximately 12.4 kDa, as well as increases the size and alters the shape of PFF-induced aggregates. This indicates that [AgI(μ-L)] 3 impacts aggregation in a manner different from HL and may serve as a novel tool for studying C-terminal truncation related aggregation chemistry.

DOI: https://doi.org/10.1101/2025.10.01.679869
J Neuroimmune Pharmacol. 2025 Nov 20. 20(1): 105

The Ubiquitin-Proteasome System in Brain Disorders: Pathogenic Pathways, Post-Translational Tweaks, and Therapeutic Frontiers.

Rohan Gupta, M Yasmin Begum, Reetesh Kumar, Jyoti Gupta, Rupak Nagraik, Siva Parsad Panda, Mosleh Mohammad Abomughaid, Sorabh Lakhanpal, Avinash D, Riyaz Ali M Osmani, Niraj Kumar Jha.

  Ubiquitination is a key enzymatic process where ubiquitin molecules covalently attach to substrate proteins, regulating their degradation, trafficking, and signaling. This process ensures cellular homeostasis by controlling protein quality and abundance, and it plays a vital role in immunity, DNA repair, and the cell cycle. Further, ubiquitination involves a sophisticated network of enzymes, domains, and receptors, providing pathway flexibility. However, dysregulation of ubiquitination due to aberrant enzyme function is implicated in various disorders, including cancer, diabetes, stroke, and neurodegenerative diseases (NDDs). Additionally, the ubiquitin-proteasome system (UPS) not only mediates protein degradation but also influences inflammation and subcellular localization. This review explores the pivotal role of ubiquitination and deubiquitination enzymes in the onset and progression of NDDs. It highlights their involvement in protein aggregation, mitochondrial impairment, neuroinflammation, and altered synaptic function. Special focus is placed on mutations in E3 ligases (e.g., E3 ubiquitin ligase encoded by PARK2 (Parkin), C-terminus of Hsp70-interacting protein (CHIP)) and deubiquitinases (e.g., USP14, ubiquitin C-terminal hydrolases (UCHL1)), which disrupt proteostasis and lead to the accumulation of neurotoxic proteins, such as Aβ, tau, α-synuclein, and mHtt. Moreover, post-translational modifications (PTMs), including phosphorylation, acetylation, and oxidative stress, further modulate UPS activity and disease progression. Lastly, the review also evaluates emerging therapeutic strategies aimed at restoring proteostasis, including proteasome-targeting small molecules (e.g., bortezomib, IU1-47), natural compounds (e.g., curcumin, resveratrol), RNA-based therapies (e.g., miR-101, circHIPK3), and dietary approaches (e.g., Mediterranean and ketogenic diets), offering a foundation for future neurodegenerative disease treatment.

Keywords:  Deubiquitinating enzymes; Neurodegenerative diseases; Post-translational modifications; Therapeutic agents; Ubiquitin proteasome system; Ubiquitinating enzymes

DOI:  https://doi.org/10.1007/s11481-025-10258-7
Biochim Biophys Acta Proteins Proteom. 2025 Nov 19. pii: S1570-9639(25)00054-8. [Epub ahead of print] 141116

Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases.

Nagma Parveen, Faizan Abul Qais, Mohammad Faheem.

  Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with -11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA282-292 oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ16-22) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.

Keywords:  Amyloid-beta; Diosgenin; Human serum albumin; Molecular dynamics simulation: ThT fluorescence; Protein aggregation

DOI:  https://doi.org/10.1016/j.bbapap.2025.141116
Small Sci. 2025 Nov;5(11): 2500345

Kinetic Mechanism of Substoichiometric Inhibition of Huntingtin Exon-1 Protein Aggregation by Selenium Nanoparticles.

Francesco Torricella, Vitali Tugarinov, G Marius Clore.

  Accumulation of huntingtin exon-1 protein (httex1) fibrils within neurons occurs when the polyglutamine region exceeds ≈35 residues and is responsible for Huntington disease, a fatal neurodegenerative condition. Recent work has shown that selenium nanoparticles (SeNP) are protective against neurodegeneration. Herein, the mechanistic basis for SeNP modulation of httex1 aggregation is explored. Fibril formation of httex1 entails two distinct processes on timescales differing by many orders of magnitude: prenucleation oligomerization on the microsecond timescale to generate a low population of transient tetramers that undergo slow (hours timescale) unimolecular conversion into elongation-competent nuclei, followed by elongation and secondary nucleation. Using NMR spectroscopy, fluorescence immunostaining, and transmission electron microscopy, the interaction of SeNPs with two httex1 protein constructs, httex1Q7 and httex1Q35 containing 7 and 35 glutamine repeats, respectively, is studied. httex1Q7 undergoes transient prenucleation tetramerization but remains largely monomeric over a period of weeks, while httex1Q35 forms fibrils within a period of hours. It is shown that SeNPs reduce the rate of fibril formation substoichiometrically with respect to monomer by selectively targeting and binding with nanomolar affinity to the extendable ends of elongation-competent species of httex1Q35, thereby reducing the pool of free extendable ends.

Keywords:  Huntington's disease; inhibition of fibril formation; protein aggregation; selenium nanoparticles

DOI:  https://doi.org/10.1002/smsc.202500345
Mol Neurobiol. 2025 Nov 19. 63(1): 87

Synuclein Proteoforms: Role in Health and Disease.

Fatima Tu Zahra, Hooreen Kayani, Samra Noreen, Aneeqa Noor, Saima Zafar.

  Synucleins α, β, and γ are inherently disordered proteins that play essential roles in neuronal physiology and are increasingly recognized as key players in neurodegenerative disease mechanisms. The molecular basis of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, is the pathological aggregation and misfolding of synucleins. However, the biological significance of the diverse synuclein proteoforms that result from alternative splicing, extensive post-translational modifications, and conformational heterogeneity is still not fully understood. This review systematically incorporates current knowledge of the structural and functional diversity of synuclein proteoforms, highlighting their molecular interactions and aggregation pathways. We investigate the regulatory effects of β and γ-synucleins (β-syn and γ-syn), which have different physiological functions and clinical applications in addition to influencing α-synuclein (α-syn) aggregation. In addition to synucleins' involvement in the central nervous system, recent findings show their role in immune regulation and functions in peripheral tissues, highlighting their systemic relevance. Controversial aspects, such as the mechanisms of prion-like propagation, proteoform-specific toxicity, and differential cellular vulnerability, are thoroughly analyzed. Synuclein proteoforms have been thoroughly characterized due to developments in molecular imaging and proteomic techniques, opening the door for targeted treatment approaches. Developing novel treatments for mitigating the progression of synucleinopathies and enhancing patient outcomes requires an understanding of the complex biology of synuclein proteoforms. The goal of this study is to present a thorough framework that connects translational research and molecular neurobiology in disorders related to synuclein.

Keywords:  PTMs; Protein misfolding; Proteoforms; Synuclein; Synucleinopathies

DOI:  https://doi.org/10.1007/s12035-025-05359-6
Nat Commun. 2025 Nov 19. 16(1): 10172

Controlling interfacial protein adsorption, desorption and aggregation in biomolecular condensates.

Brent S Visser, Merlijn H I van Haren, Wojciech P Lipiński, Kirsten A van Leijenhorst-Groener, Mireille M A E Claessens, Marcos V A Queirós, Carlos H I Ramos, Jorine Eeftens, Evan Spruijt.

Aggregation of amyloidogenic proteins is linked to age-related diseases. The presence of interfaces can affect their aggregation mechanism, often speeding up aggregation. α-Synuclein (αSyn) can adsorb to biomolecular condensates, leading to heterogenous nucleation and faster aggregation. Understanding the mechanism underlying localization of amyloidogenic proteins at condensate interfaces is crucial for developing strategies to prevent or reverse their binding. We show that αSyn localization to the surface of peptide-based heterotypic condensates is an adsorption process governed by the protein's condensate-amphiphilic nature, and the condensate surface charge. Adsorption occurs reversibly in multiple layers and plateaus at micromolar concentrations. Based on these findings, we rationally design three strategies to modulate αSyn accumulation: (i) addition of biomolecules that decrease the condensate ζ-potential, such as NTPs and RNA, (ii) competitive adsorption of proteins targeting the condensate interface, such as G3BP1, DDX4-YFP, EGFP-NPM1, Hsp70, Hsc70, and (iii) preferential adsorption of αSyn to membranes. Removing αSyn from the condensate interface slows aggregation, highlighting potential cellular control over protein adsorption and implications for therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-65030-5
ACS Chem Neurosci. 2025 Nov 17.

Native PEG-PLGA Attenuates β-Amyloid Aggregation and Toxicity under In Vitro Conditions.

Mallesh Rathnam, Haley Hunter, Pallabi Sil Paul, Ralf Schirrmacher, Michael J Serpe, Satyabrata Kar.

  Self-aggregation of amyloid-β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD), the most prevalent cause of dementia affecting the elderly population. The development of an effective treatment for AD pathology remains elusive due to the presence of the blood-brain barrier (BBB) and the heterogeneous nature of disease progression. Recently, we reported that FDA-approved native poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles without any conjugated/encapsulated agent can attenuate Aβ aggregation/toxicity in cellular and animal models of AD. Given the limitation associated with the fast clearance of the native PLGA by the reticuloendothelial system (RES), in the present study, we synthesized PEGylated native PLGA nanoparticles (PEG-PLGA-1) to reduce their clearance via the RES and evaluated their effects on Aβ aggregation/toxicity after biochemical and structural characterization. Determined with Thioflavin T kinetic assay, dynamic light scattering and fluorescence imaging, it was revealed that the native PEG-PLGA-1, which exhibits increased stability, not only inhibits the aggregation of Aβ peptides, but also triggers the disassembly of Aβ aggregates. Additionally, we showed that PEG-PLGA-1 are nontoxic and can significantly enhance the viability of mouse primary cortical cultured neurons against Aβ-mediated toxicity. Collectively, these results suggest that native PEG-PLGA-1 nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates and can protect neurons against Aβ-mediated toxicity, thus suggesting their unique therapeutic potential in the treatment of AD pathology.

Keywords:  Alzheimer’s disease; Aβ aggregation; Aβ disassembly; PEG−PLGA nanoparticles; neuroprotection; protein aggregation

DOI:  https://doi.org/10.1021/acschemneuro.5c00379
NAR Mol Med. 2025 Apr;2(2): ugaf012

The role of RNA in the nanoscale organization of α-synuclein phase separation.

Sabrina Zappone, Eleonora Perego, Jakob Rupert, Elsa Zacco, Eli Slenders, Gian Gaetano Tartaglia, Giuseppe Vicidomini.

The cellular accumulation of α-synuclein (aS) aggregates is a hallmark of several neurodegenerative diseases. Recent studies suggest that the aberrant transition of monomeric aS into solid-like aggregates may occur through an intermediate liquid-like state, where the protein partitions between dense and dilute phases. Although aS is not typically recognized as an RNA-binding protein, it can bind RNA under aggregation conditions, but its impact on aS liquid-like phases remains unexplored. Employing a combination of fluorescence spectroscopy techniques, we investigated aS mobility in both phases in the presence of RNA. Our analysis revealed the formation of nanoclusters involved in initiating phase separation and uncovered heterogeneity within the dense phase, discovering that aS molecules exist in two distinct mobility states. Additionally, we demonstrated that RNA induces morphological changes and promotes the liquid-to-solid transition of aS dense phase. These findings underscore the active role of RNA in modulating aS phase transitions.

DOI: https://doi.org/10.1093/narmme/ugaf012
ACS Med Chem Lett. 2025 Nov 13. 16(11): 2171-2174

LRRK2 Degraders for Parkinson's Disease and Inflammation: Tau and α‑Synuclein Degraders for Neurodegeneration.

Anna C Renner, Robert B Kargbo.

Two complementary PROTAC classesbenzimidazole-anchored degraders of LRRK2 and pyrrolopyridine-based scaffolds for tau and α-synuclein clearancedemonstrate subnanomolar degradation potency, improved SAR over phthalimide comparators, and translational positioning for Parkinson's disease and tauopathies. Together, they highlight the therapeutic convergence of chemically differentiated anchors and robust degradation assays in advancing CNS-targeted protein degradation modalities.

DOI: https://doi.org/10.1021/acsmedchemlett.5c00594
Nat Commun. 2025 Nov 21. 16(1): 10239

Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration.

Xun Sun, Debasis Saha, Xue Wang, Cecilia Mörman, Rebecca Sternke-Hoffmann, Juan Atilio Gerez, Fátima Herranz-Trillo, Roland Riek, Wenwei Zheng, Jinghui Luo.

Spermine, a pivotal player in biomolecular condensation and diverse cellular processes, has emerged as a focus of investigation in aging, neurodegeneration, and other diseases. Despite its significance, the mechanistic details of spermine remain incompletely understood. Here, we describe the distinct modulation by spermine on Alzheimer's Tau and Parkinson's α-synuclein, elucidating their condensation behaviors in vitro and in vivo. Using biophysical techniques including time-resolved SAXS and NMR, we trace electrostatically driven transitions from atomic-scale conformational changes to mesoscopic structures. Notably, spermine extends lifespan, ameliorates movement deficits, and restores mitochondrial function in C. elegans models expressing Tau and α-synuclein. Acting as a molecular glue, spermine orchestrates in vivo condensation of α-synuclein, influences condensate mobility, and promotes degradation via autophagy, specifically through autophagosome expansion. This study unveils the interplay between spermine, protein condensation, and functional outcomes, advancing our understanding of neurodegenerative diseases and paving the way for therapeutic development.

DOI: https://doi.org/10.1038/s41467-025-65426-3
Cell Rep. 2025 Nov 14. pii: S2211-1247(25)01336-1. [Epub ahead of print]44(11): 116564

In situ amplification of α-synuclein amyloid fibril reveals a distinct polymorph related to Parkinson's disease and dementia with Lewy body.

Tianyi Cao, Qinyue Zhao, Yuxuan Yao, Kaien Liu, Youqi Tao, Shiran Lv, Feng Gao, Yong Shen, Chao Ma, Wenying Qiu, Cong Liu, WeiDong Le, Dan Li.

  High-resolution structure determination of ex vivo amyloid fibrils offers critical mechanistic insights into amyloid polymorphism and heterogeneity of neurodegenerative diseases. However, purifying amyloid fibrils from diseased brains may favor certain polymorphs over others. Here, instead of purifying fibrils, we used in situ amplification (ISA) of α-synuclein (α-syn) fibrils in brain homogenates. Cryoelectron microscopy (cryo-EM) structural analysis of the ISA fibrils from patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) reveal polymorphic fibril ensembles of each case including fibrils with morphologies similar to previously reported Lewy fold, as well as many others. Remarkably, we determine the high-resolution structure of a distinct polymorph (ISA-P1) that differs from the Lewy fold but is similar to those of multiple system atrophy (MSA) and juvenile-onset synucleinopathy (JOS). Our work supports the existence of alternative α-syn fibril polymorphs in PD and DLB, some of which may share common prototypical folds across various synucleinopathies.

Keywords:  CP: Neuroscience; amyloid fibril; in situ amplification; neurodegenerative disease; pathological heterogeneity; structural polymorphism

DOI:  https://doi.org/10.1016/j.celrep.2025.116564
Adv Sci (Weinh). 2025 Nov 19. e09773

Morphological and Hyperphosphorylation Transitions of Nanoscale Tau Aggregates in Alzheimer's Disease.

Adriana N Santiago-Ruiz, Siewert Hugelier, Gabriela L Correa, Charles R Bond, Edward B Lee, Melike Lakadamyali.

  Tau aggregation plays a critical role in Alzheimer's Disease (AD), where neurofibrillary tangles (NFTs) are a pathological hallmark. While much attention is given to NFTs, emerging evidence highlights nano-sized tau oligomers as toxic entities. Using super-resolution microscopy, we visualized nano-sized tau aggregates (nano-aggregates) in human postmortem brain tissues from intermediate and advanced AD, Primary Age-Related Tauopathy (PART), and controls lacking tau pathology. Surprisingly, tau nano-aggregates hyperphosphorylated at threonine 231 (p-T231) and threonine 181 (p-T181)are detected in control cases, whereas hyperphosphorylated serine 202/threonine 205 (p-S202/T205)nano-aggregates are specifically associated with AD and, to a lesser extent, observed in PART. This finding suggests that distinct hyperphosphorylation signatures distinguish physiological from pathological nano-aggregates. Moreover, nano-aggregates exhibit morphological differences between AD and non-AD conditions, increasing in size and complexity in AD. In advanced AD, nano-aggregates typically contain multiple distinct hyperphosphorylated residues, whereas intermediate AD nano-aggregates are predominantly marked by a single hyperphosphorylated residue. These findings reveal novel transitions in the morphology and hyperphosphorylation states of tau nano-aggregates as they shift from physiological to pathological forms. The ability to detect and profile physiological and pathological nanoscale tau aggregates in human brain tissues opens new avenues for studying the molecular underpinnings of tauopathies.

Keywords:  Alzheimer's disease; DNA‐PAINT; hyperphosphorylation; nano‐aggregates; super‐resolution microscopy; tau aggregation

DOI:  https://doi.org/10.1002/advs.202509773
Anal Chem. 2025 Nov 17.

Discrimination of Formation Processes of Amyloid β Fibrils with Distinct Morphologies Using Rheo-NMR Spectroscopy.

Daichi Morimoto, Erik Walinda, Soki Shimizu, Jana Farré, Masahiro Shirakawa.

The accumulation of abnormal protein fibrillar aggregates is a hallmark of various neurodegenerative diseases. Notably, a single type of protein species can form fibrils with distinct morphologies, and recent studies have linked fibril polymorphism to variations in disease symptoms. However, the mechanisms underlying the formation and structural distinction of these morphologies remain elusive. Here, we monitored the real-time formation of amyloid-β peptide (Aβ1-40) fibrils with two distinct morphologies at atomic resolution using Rheo-NMR spectroscopy, a method which enables the observation of protein NMR signals under shear flow. Under quiescent conditions, Aβ1-40 formed relatively thick fibrils, accompanied by structural rigidification in the region spanning from residues E22 to A30. In contrast, fibrils formed under shear were thinner, with Aβ1-40 adopting more elongated conformations. Molecular dynamics simulations corroborated the NMR results, indicating that shear flow impedes essential structural transitions required for one specific fibril morphology, and instead promoted formation of a different morphology. Intriguingly, a fluorinated amyloid-binding dye, FSB, distinguished these two types of Aβ1-40 fibrils and their formation processes based on its 19F NMR signals. These findings not only provide atomic-level insights into the formation of different fibril morphologies but also propose a new framework for distinguishing pathological fibril types relevant to neurodegenerative disease.

DOI: https://doi.org/10.1021/acs.analchem.5c04379