bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–09–14
sixteen papers selected by
Verena Kohler, Umeå University
  1. Competing chaperone pathways in α-synuclein disaggregation and aggregation dynamics.
  2. In Vitro Evaluation of Amide-Linked Coumarin Scaffolds for the Inhibition of α‑Synuclein and Tau Aggregation.
  3. α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation.
  4. Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones.
  5. Membranes as targets and modifiers of mutant huntingtin aggregation.
  6. Genetic code expansion and enzymatic modifications as accessible methods for studying site-specific post-translational modifications of alpha-synuclein and tau.
  7. Glycated Alpha-Synuclein Assemblies Cause Distinct Parkinson's Disease Pathogenesis in Mice.
  8. Dissecting the Molecular Determinants of α-synuclein Phase Separation and Condensate Aging: The Pivotal Role of β-Sheet-Rich Motifs.
  9. The bacterial OMP amyloids modulate α-synuclein and amyloid-β aggregation.
  10. Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?
  11. Acetylation Mimetic and Null Mutations Within the Filament Core of P301L Tau Have Varied Effects on Susceptibility to Seeding and Aggregation.
  12. Contemporary trends in targeted protein degradation for neurodegenerative diseases.
  13. Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders.
  14. Methylglyoxal Aggregates α-Synuclein by Inhibiting SIRT1-Hif-1α in Intestinal Enteroendocrine Cells.
  15. Antibodies raised against a structurally defined Aβ oligomer mimic protect human iPSC neurons from Aβ toxicity at sub-stoichiometric concentrations.
  16. Deficiency of N1-Adenine Methyltransferase Aggravates RNA and Protein Aggregation.
  1. Protein Sci. 2025 Oct;34(10): e70296
    Competing chaperone pathways in α-synuclein disaggregation and aggregation dynamics.
    Nicola K Auld, Shannon McMahon, Nicholas R Marzano, Antoine M van Oijen, Heath Ecroyd.
      The aggregation of the protein α-synuclein into amyloid fibrils and their subsequent deposition into large proteinaceous inclusions is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease. Molecular chaperones, including the small heat-shock proteins (sHsps) and the Hsp70 chaperone system, are known to interact with α-synuclein fibrils, preventing further aggregation and disaggregating fibrillar species, respectively. However, it remains unclear if sHsps co-operate with the Hsp70 chaperones to potentially improve the kinetics or effectiveness of Hsp70-mediated disaggregation and how disaggregation kinetics are influenced by aggregation-prone α-synuclein monomers. Using thioflavin-T assays, we demonstrate that the sHsps Hsp27 (HSPB1) and αB-crystallin (HSPB5) do not synergize with the Hsp70 chaperones during α-synuclein seed fibril disaggregation. Moreover, the addition of monomeric α-synuclein with fibril seeds results in increased aggregation that overwhelms Hsp70-mediated disaggregation. Overall, these results suggest that while Hsp70 and sHsp chaperones are independently capable of binding to and inhibiting fibril elongation, they do not have synergistic effects on disaggregation. Furthermore, Hsp70-mediated disaggregation is ineffectual in the presence of physiological concentrations of α-synuclein monomers, conditions that actually lead to further α-synuclein aggregation. Overall, these data may offer insight into factors that lead to the failure of the Hsp70 chaperones to clear cells of α-synuclein aggregates that lead to neurodegenerative disease.
    Keywords:  Hsp27; Hsp70 system; disaggregation; molecular chaperones; αB‐crystallin; α‐Synuclein
    DOI:  https://doi.org/10.1002/pro.70296
  2. ACS Omega. 2025 Sep 02. 10(34): 38498-38514
    In Vitro Evaluation of Amide-Linked Coumarin Scaffolds for the Inhibition of α‑Synuclein and Tau Aggregation.
    Taiwo A Ademoye, Susantha K Ganegamage, Behrad Masoudi, Omnia M H Ibrahium, Heba Alnakhala, Arati Tripathi, Ulf Dettmer, Raluca Ostafe, Babak Borhan, Jessica S Fortin.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative disorders characterized by continuous loss of functional neurons. The numbers of AD and PD patients will likely double by 2060 and 2040, reaching 13.9 and 1.2 million, respectively, in the US alone. Although both AD and PD are multifactorial in origin, the accumulation of misfolded proteins such as α-synuclein (α-syn) and tau contribute to nerve function disruption. Therefore, inhibition of α-syn and tau aggregation via small-molecule disruptors of oligomer and fibril formation presents a promising method for treating AD and PD. Coumarin scaffolds possess a wide range of bioactivities, particularly their antiamyloidogenic potential, which was explored in this study. Our previous work demonstrated that amide linkers and amino indole moieties have antioligomer and antifibrillar effects. This study involves coupling the coumarin scaffold with various aromatic moieties, including aminoindoles, methoxy-substituted phenyl, and polyhydroxy aromatic functionalities, via an amide linker for establishing the structural activity relationship (SAR) for the inhibition of oligomer and fibril formation. In total, 38 coumarin-based amide compounds were prepared to first explore the antifibrillar activity on recombinant α-syn. The best compounds were then tested to assess the antioligomer effects, tau aggregation activity, inclusion inhibition, and dimerization in cells. Biophysical methods such as thioflavin T (ThT) fluorescence assays, photoinduced cross-linking of unmodified proteins (PICUP), survival assays, and electron microscopic observations were used to evaluate the inhibitory effects of analogs on α-syn and tau aggregation. The coumarin-amide-dihydroxybenzene derivatives demonstrated superior effects on the inhibition of α-syn aggregation when compared with the coumarin-amide-indole derivatives. The methoxy (nondemethylated) counterparts of compounds 13 and 17 failed at reducing α-syn fibril formation. The coumarin-amide-dihydroxybenzene derivatives 13 and 17, exhibited different degrees of inhibition on the α-syn oligomer and inclusion formation. Compound 13 inhibited tau (2N4R isoform) oligomer formation and reduced tau dimerization in a cell-based assay. In conclusion, the results presented herein will guide future optimization of molecules with inhibitory effects on prone-to-aggregate proteins and may pave the way for disease-modifying treatments for neurodegenerative disorders.
    DOI:  https://doi.org/10.1021/acsomega.5c02435
  3. Mol Cell. 2025 Sep 10. pii: S1097-2765(25)00707-5. [Epub ahead of print]
    α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation.
    Cole S Sitron, Victoria A Trinkaus, Ana Galesic, Maximilian Garhammer, Patricia Yuste-Checa, Ulrich Dransfeld, Dennis Feigenbutz, Jiuchun Zhang, Larysa Ivashko, Irina Dudanova, J Wade Harper, F Ulrich Hartl.
      α-Synuclein aggregation is a hallmark of Parkinson's disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregation. Intracellular aggregates sequester numerous proteins, including subunits of the endosomal sorting complexes required for transport (ESCRT)-III system for endolysosome membrane repair, but the toxic effects of these events remain poorly understood. Using cellular models and in vitro reconstitution, we found that α-synuclein fibrils interact with a conserved α-helix in ESCRT-III proteins. This interaction sequesters ESCRT-III subunits and triggers their proteasomal destruction in a process of "collateral degradation." These twin mechanisms deplete the available ESCRT-III pool, initiating a toxic feedback loop. The ensuing loss of ESCRT function compromises endolysosome membranes, thereby facilitating escape of aggregate seeds into the cytoplasm, facilitating a "second wave" of templated aggregation and ESCRT-III sequestration. We suggest that collateral degradation and the triggering of self-perpetuating systems are general mechanisms of sequestration-induced proteotoxicity.
    Keywords:  CHMP2B; ESCRT; ESCRT-III; Parkinson’s disease; aggregation; lysosome; protein aggregate spreading; proteostasis; sequestration; α-synuclein
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.022
  4. Biomed Pharmacother. 2025 Sep 08. pii: S0753-3322(25)00725-5. [Epub ahead of print]191 118531
    Targeting protein misfolding in Alzheimer's disease: The emerging role of molecular chaperones.
    Anushka Sharma, Shriyansh Srivastava, Pranav Gupta, Sathvik Belagodu Sridhar, Mohd Tariq, G S N Koteswara Rao, Sachin Kumar, Tabarak Malik.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline and the accumulation of misfolded proteins, including amyloid-beta and hyperphosphorylated tau, which impair neuronal function and promote cell death. These misfolded proteins disrupt proteostasis by forming toxic aggregates that exacerbate disease progression. Molecular chaperones, such as heat shock proteins, actively maintain protein homeostasis by assisting in proper folding, preventing aggregation, and promoting the clearance of misfolded proteins. Dysfunction in chaperone systems contributes to the pathogenesis of AD, positioning them as promising therapeutic targets. Recent research has explored chaperone-based interventions, including small molecules, gene therapies, and autophagy and proteasomal degradation modulators, to restore protein balance. Advances in high-throughput screening and omics technologies have accelerated the identification of potential chaperone modulators. Despite these developments, the complexity of AD and the shortcomings of existing disease models make it difficult to translate preclinical results into successful clinical treatments. This review critically examines the role of protein misfolding and chaperone dysfunction in AD, evaluates emerging therapeutic strategies, and highlights current clinical trials, aiming to bridge molecular mechanisms with translational opportunities in the pursuit of novel AD treatments.
    Keywords:  Alzheimer’s disease; Molecular chaperones; Protein homeostasis; Protein misfolding; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.biopha.2025.118531
  5. Trends Biochem Sci. 2025 Sep 09. pii: S0968-0004(25)00194-X. [Epub ahead of print]
    Membranes as targets and modifiers of mutant huntingtin aggregation.
    Justin Legleiter.
      Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene, resulting in an expanded polyglutamine (polyQ) tract in HTT protein. Expanded polyQ tracts cause mutant HTT (mHTT) to aggregate and accumulate as cellular inclusions. Recent studies highlight the interactions between mHTT and different cellular membranes that contribute to HD pathogenesis. Beyond being targets for mHTT-induced damage, membranes modify mHTT aggregation in a complex manner. This review explores the membrane abnormalities observed in a variety of HD models and the interplay between binding to and subsequent aggregation of mHTT on membranes, with an emphasis on N-terminal mHTT fragments. Understanding mHTT-lipid interactions may provide potential targets for therapeutic intervention that would complement other efforts.
    Keywords:  Huntington’s disease; amyloid; lipids; neurodegeneration; polyglutamine
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.005
  6. Protein Sci. 2025 Oct;34(10): e70302
    Genetic code expansion and enzymatic modifications as accessible methods for studying site-specific post-translational modifications of alpha-synuclein and tau.
    Ibrahim G Saleh, Marie Shimogawa, Jennifer Ramirez, Bernard Abakah, Yarra Venkatesh, Honey Priya James, Ming-Hao Li, Sarah A Louie, Marshall G Lougee, Wai-Kit Chia, Christopher Brue, Richard B Cooley, Ryan A Mehl, Tobias Baumgart, Robert H Mach, David Eliezer, Elizabeth Rhoades, E James Petersson.
      Alpha-synuclein (αS) and tau play important roles in the pathology of Parkinson's disease and Alzheimer's disease, respectively, as well as numerous other neurodegenerative diseases. Both proteins are classified as intrinsically disordered proteins (IDPs), as they have no stable structure that underlies their function in healthy tissue, and both proteins are prone to aggregation in disease states. There is substantial interest in understanding the roles that post-translational modifications (PTMs) play in regulating the structural dynamics and function of αS and tau monomers, as well as their propensity to aggregate. While there have been many valuable insights into site-specific effects of PTMs garnered through chemical synthesis and semi-synthesis, these techniques are often outside of the expertise of biochemistry and biophysics laboratories wishing to study αS and tau. Therefore, we have assembled a primer on genetic code expansion and enzymatic modification approaches to installing PTMs into αS and tau site-specifically, including isotopic labeling for NMR and fluorescent labeling for biophysics and microscopy experiments. These methods should be enabling for those wishing to study authentic PTMs in αS or tau as well as the broader field of IDPs and aggregating proteins.
    Keywords:  alpha‐synuclein; genetic code expansion; post‐translational modification; tau
    DOI:  https://doi.org/10.1002/pro.70302
  7. ACS Chem Neurosci. 2025 Sep 12.
    Glycated Alpha-Synuclein Assemblies Cause Distinct Parkinson's Disease Pathogenesis in Mice.
    Akshaya Rajan, Anish Varghese, Shaliya Puthanveedu Hashardeen, Ann Teres Babu, Vinesh Vijayan, Poonam Thakur.
      Alpha-synuclein (α-Syn) misfolding and aggregation are key drivers of Parkinson's disease (PD) pathology. Mutations and certain post-translational modifications impact its aggregation propensity and pathogenicity. Glycation, a nonenzymatic modification enhanced during hyperglycemia and aging, both known risk factors for PD, has been implicated in α-Syn pathology. Although preformed α-Syn fibrils induce PD-like phenotypes in mice, the impact of glycation on their pathogenicity is unclear. In the current study, we glycated α-Syn using methylglyoxal (MGO), a potent glycating agent, resulting in altered biophysical characteristics in comparison to nonglycated α-Syn. Glycation inhibited the formation of typical β sheet structures under aggregating conditions. Despite that, glycated α-Syn assemblies induced dopaminergic neurodegeneration and neuroinflammation to a similar extent as the nonglycated α-Syn fibrils upon their injection in the mouse substantia nigra (SN). However, these glycated assemblies triggered higher neuroinflammation and increased accumulation of receptor for advanced glycation end products (RAGE) compared to nonglycated fibrils. Consequently, an earlier onset of neuromuscular deficits and anxiety was observed in these mice. Thus, glycation of α-Syn causes distinct PD-associated pathology compared to nonglycated α-Syn, causing an earlier onset of motor symptoms. These findings provide insight into how the glycation of α-Syn due to hyperglycemia may contribute to an increased risk of PD in diabetic populations.
    Keywords:  Advanced Glycation End Products; Diabetes; Hyperglycemia; Neuroinflammation; Phospho-synuclein; Receptor for Advanced Glycation End Products; Substantia Nigra
    DOI:  https://doi.org/10.1021/acschemneuro.5c00428
  8. Adv Sci (Weinh). 2025 Sep 08. e11545
    Dissecting the Molecular Determinants of α-synuclein Phase Separation and Condensate Aging: The Pivotal Role of β-Sheet-Rich Motifs.
    Yiming Tang, Jitao Wen, Zhongyuan Yang, Yifei Yao, Shaoshuai He, Jiyuan Zeng, Xuewei Dong, Qin Qiao, Yun Zhou, Sarah Perrett, Si Wu, Guanghong Wei.
      Emerging evidence indicates that liquid-liquid phase separation of α-synuclein occurs during the nucleation step of its aggregation, a pivotal step in the onset of Parkinson's disease. Elucidating the molecular determinants governing this process is essential for understanding the pathological mechanisms of diseases and developing therapeutic strategies that target early-stage aggregation. While previous studies have identified residues critical for α-synuclein amyloid formation, the key residues and molecular drivers of its phase separation remain largely unexplored. Herein, multiscale simulations and experimental approaches are employed to uncover the molecular determinants dictating α-synuclein phase separation and the pre-solidification of its condensates. Seven motifs are identified that exhibit high β-sheet propensity in the monomeric state of α-synuclein and progressively increase in β-sheet content during condensation. Notably, two C-terminal motifs engage in a percolated network of intermolecular interactions through transient hydrogen bonds, contributing to the phase boundary properties. Deletion of these motifs reduces the phase separation ability of α-synuclein, underscoring their essential roles in this process. Together, the findings reveal crucial phase separation hotspots and shed light on the molecular mechanism underlying α-synuclein phase separation, offering significant insights and novel potential therapeutic targets for Parkinson's disease.
    Keywords:  Parkinson's disease; condensate aging; liquid‐liquid phase separation; molecular dynamics simulation; α‐synuclein
    DOI:  https://doi.org/10.1002/advs.202511545
  9. Int J Biol Macromol. 2025 Sep 06. pii: S0141-8130(25)08042-0. [Epub ahead of print]327(Pt 2): 147485
    The bacterial OMP amyloids modulate α-synuclein and amyloid-β aggregation.
    Maksim I Sulatsky, Mikhail V Belousov, Olesya V Stepanenko, Olga V Stepanenko, Ekaterina V Mikhailova, Haidar Fayoud, Anton A Nizhnikov, Anna I Sulatskaya.
      Growing evidence links gut microbiota to neurodegenerative diseases, yet direct molecular interactions between bacterial and host amyloid proteins remain incompletely understood. Bacterial amyloids represent an understudied yet potentially critical component of gut-brain communication in neurodegeneration. Here, we provide the first investigation of whether amyloids formed by outer membrane proteins (OMPs) of enterobacteria can modulate neurodegeneration-associated protein aggregation. We examined the effects of pre-formed amyloid fibrils from OmpC and OmpF of Escherichia coli and Salmonella enterica on fibrillogenesis of α-synuclein and amyloid-β, whose pathological accumulation in brain is associated with Parkinson's and Alzheimer's diseases, respectively. Using a comprehensive array of physicochemical methods, we discovered that bacterial OMP amyloids altered the structural properties and clustering tendency of mammalian amyloids in a target-specific manner. In particular, for α-synuclein, OMP amyloids modified the irregular "fuzzy coat" surrounding the ordered β-core, increasing fibril clustering without affecting core structure, quantity, or cytotoxicity. In contrast, amyloid-β fibrils showed more extensive structural changes, with modifications to both the "fuzzy coat" and β-sheet core, accompanied by a decreased clustering tendency and significantly reduced toxicity for mammalian neuroblastoma and epithelial adenocarcinoma cell lines. Our findings demonstrate that amyloids formed from OMPs produced by Enterobacteriaceae species represent a previously unrecognized class of amyloid modulators capable of influencing pathological aggregation of mammalian proteins through intermolecular contacts. These results open a discussion on the dual role of bacterial amyloids in neurodegeneration, as they may be capable not only of promoting pathological amyloidogenesis but also of mitigating the toxic effects of host amyloid aggregates.
    Keywords:  Amyloid; Amyloid-β; Fibrillogenesis; Gut-brain; Microbiome; Neurodegeneration; Outer membrane protein; Porins; α-Synuclein
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147485
  10. Cells. 2025 Aug 30. pii: 1356. [Epub ahead of print]14(17):
    Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?
    Urszula Kochman, Hanna Sitka, Julia Kuźniar, Magdalena Czaja, Patrycja Kozubek, Jan Aleksander Beszłej, Jerzy Leszek.
      Alzheimer's disease (AD) is marked by the pathological aggregation of amyloid β (Aβ) and tau proteins. Emerging research reveals that these proteins undergo liquid-liquid phase separation (LLPS), forming biomolecular condensates that promote aggregation and neurotoxicity. These phase-separated structures reshape the intracellular environment, facilitating protein misfolding and spreading. This review highlights recent advances in understanding the role of condensates in AD pathogenesis and explores novel therapeutic strategies targeting condensate dynamics. Promising approaches include small molecules that disrupt LLPS, epigenetic drugs influencing nuclear condensates, and compounds like DDL 920 and RI AG03 that modulate tau phase separation and neuroinflammation, respectively. Additionally, anti-inflammatory agents, such as nucleotide reverse transcriptase inhibitors (NRTIs), offer potential for upstream intervention. Targeting biomolecular condensates presents a next-generation strategy for AD treatment. Future research should focus on in vivo profiling of condensate composition, biomarker development, and the development of patient-specific therapies to enable early, disease-modifying interventions.
    Keywords:  Alzheimer’s disease; biomolecular condensates; liquid–liquid phase separation; neuronal death
    DOI:  https://doi.org/10.3390/cells14171356
  11. J Neurochem. 2025 Sep;169(9): e70221
    Acetylation Mimetic and Null Mutations Within the Filament Core of P301L Tau Have Varied Effects on Susceptibility to Seeding and Aggregation.
    Ethan D Smith, Jose Torrellas, Robert McKenna, Quan Vo, Mario Mietzsch, David R Borchelt, Stefan Prokop, Paramita Chakrabarty.
      The two most prominent post-translational modifications of pathologic tau are Ser/Thr/Tyr phosphorylation and Lys acetylation. Whether acetylation impacts the susceptibility of tau to templated seeding in diseases like Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP) is largely uncharacterized. Towards this, we examined how acetylation mimicking or nullifying mutations on five sites of tau (K311, K353, K369, K370, K375), located within the tau filament core, influenced the susceptibility of P301L (PL) tau to seeds from AD (AD-tau) or PSP (PSP-tau) brain donors in HEK293T cells. Acetyl-mimicking substitutions of individual Lys sites to Glutamine as well as mutation of all 5 sites together (PL+5K-Q and PL+5K-R) had inconsistent effects on tau seeding by AD-tau or PSP-tau seeds. Unexpectedly, mutating all 5 sites to Alanine (PL+5K-A) resulted in a tau variant that spontaneously aggregated. These aggregates were amorphous and yet able to propagate to naïve cells expressing P301L tau but not wild-type tau. Previously, we reported that a phospho-mimetic S305E mutation in PL tau abrogated seeding by AD-tau but not PSP-tau seeds in the HEK293T cells. To assess how changes in acetylation and phosphorylation together could influence seeding, we combined the S305E and the 5K-Q mutations in PL tau, creating a variant that retained specificity for PSP-tau seeds over AD-tau seeds. Our findings indicate that phosphorylation of tau at Ser305 is a strong determinant of disease-specific tau templating, even in the presence of hyperacetylation within the fibril core domain. Overall, our findings suggest that acetylation in the tau filament core domain has limited effects on tau seeding.
    Keywords:  Alzheimer's disease; aggregation; post‐translational modification; progressive supranuclear palsy; seeding
    DOI:  https://doi.org/10.1111/jnc.70221
  12. Eur J Med Chem. 2025 Aug 29. pii: S0223-5234(25)00875-X. [Epub ahead of print]300 118110
    Contemporary trends in targeted protein degradation for neurodegenerative diseases.
    Gulshan Kumar, Vaibhav Thakur, Satish Sardana, Vinod Tiwari, Dilip Sharma, Asim Kumar.
      Neurodegenerative diseases (NDs), including Alzheimer's, Huntington's, and Parkinson's disease, are associated with significant declines in cognitive function and mobility. The accumulation of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates is a key factor in the progression of these conditions. Unfortunately, traditional small-molecule drugs face major obstacles in effectively targeting these proteins. In recent times, there has been a growing interest among researchers in the pharmaceutical field in utilizing small molecules to degrade proteins as a therapeutic strategy, specifically. This approach, also known as targeted protein degradation (TPD), has shown great potential and is gaining increasing attention. Particularly, two techniques - Proteolysis Targeting Chimeras (PROTACs) and Lysosome-Targeting Chimeras (LYTACs) - have emerged as highly promising methods for eliminating disease-associated proteins by leveraging the natural destruction processes within cells. Numerous novel TPD strategies, such as molecular glue, Antibody-based PROTAC (AbTAC), AUTOphagy-TArgeting Chimera (AUTOTAC), and bispecific aptamer chimera, are emerging alongside PROTAC and LYTAC. These cutting-edge technologies are expanding TPD's possibilities and bringing fresh insights into drug discovery. Here, we present a concise overview of the latest advancements in different TPD technologies. We delve into their potential applications in ND and strive to provide a comprehensive guide for biologists and chemists interested in exploring this rapidly evolving field.
    Keywords:  Hydrophobic tagging; LYTAC; Neurodegeneration; PROTAC; Protein degradation
    DOI:  https://doi.org/10.1016/j.ejmech.2025.118110
  13. Crit Rev Anal Chem. 2025 Sep 08. 1-29
    Exploring Thiophene-Based Pharmacophores as Emerging Therapeutics for Neurodegenerative Disorders.
    Shivank Sharma, Mukta Gupta, Shivani Sharma.
      Neurodegenerative disorders (NDD) i.e., dementia of the Alzheimer's type, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a rising worldwide epidemic driven by aging populations and characterized by progressive neuronal impairment. In the face of symptomatic therapies, disease-modifying treatments are beyond reach, for many years, at least, owing to the multifactorial origin, including protein aggregation, oxidative stress, neuroinflammation, and neurotransmitter dysregulation. Here, we point out thiophene, a five-membered heterocyclic sulfur-containing scaffold, as an underinvestigated but highly versatile pharmacophore with great potential in therapeutics of NDD. Here, we provide a systematic review of thiophene derivatives identified between 2006 and 2024, highlighting that these compounds are capable of modulating the aggregation of amyloid-β, inhibiting acetylcholinesterase, alleviating oxidative stress, inhibiting the toxicity of α-synuclein, and restoring neurotransmitter homeostasis. Specific emphasis is placed on their structural malleability, blood-brain barrier penetrability, and multi-targeting, which collectively present advantages over traditional heterocyclic templates. Progress in the areas of structure-activity relationship (SAR)-motivated design, synthetic methods, molecular docking, and preclinical assessment is reviewed, leading to the establishment of lead thiophene scaffolds with micro or nanomolar-range activity. This review also provides future directions, such as the requirement of pharmacokinetic improvement, target verification, and translational research to bridge preclinical discoveries with clinical utility. This article collectively places thiophene derivatives as an innovative chemical platform for the design of next-generation drugs for neurodegenerative diseases.
    Keywords:  Neurodegenerative disorders; SAR; thiophene
    DOI:  https://doi.org/10.1080/10408347.2025.2554239
  14. Int J Toxicol. 2025 Sep 13. 10915818251378724
    Methylglyoxal Aggregates α-Synuclein by Inhibiting SIRT1-Hif-1α in Intestinal Enteroendocrine Cells.
    Eugene Huh, Jin Myeong Kim, Seong Hye Kim, Yujin Choi, Myoung Gyu Park, Myung Sook Oh.
      Parkinson's disease (PD) is characterized by the abnormal aggregation of α-synuclein, which can originate in the gut and propagate to the brain. Recent evidence suggests a correlation between metabolic disorders, particularly diabetes, and PD pathogenesis through the gut-brain axis. Methylglyoxal (MGO), a glucose-derived metabolite produced by gut bacteria such as Proteus mirabilis, is implicated in protein misfolding and glycation. This study investigated whether MGO induced α-synuclein aggregation in intestinal enteroendocrine cells and explored the underlying mechanisms. Mouse enteroendocrine STC-1 cells were treated with MGO (0.01-1 mM) for 36 h, and changes in α-synuclein aggregation, neuronal markers, and relevant signaling pathways were assessed. MGO at 1 mM significantly reduced cell viability and neuronal marker expression, and concentrations of 0.1 and 1 mM increased α-synuclein aggregation. MGO also inhibited SIRT1 expression, leading to increased Hif-1α transcription and reduced expression of autophagy-related proteins Beclin1 and LC3B. These changes were accompanied by mitochondrial dysfunction, as evidenced by decreased Bcl2, increased cytochrome C expression, and reduced levels of the antioxidant factor HO-1. Our findings provide the first evidence that MGO directly induces α-synuclein aggregation in enteroendocrine cells via the SIRT1-Hif-1α-autophagy pathway dysregulation, establishing a potential mechanistic link between gut microbiome-derived metabolites and PD pathogenesis. These results suggest that intestinal glycation may be a critical target for preventing α-synuclein pathology originating in the gut.
    Keywords:  Parkinson’s disease; enteroendocrine cells; glycation; gut–brain axis; methylglyoxal; α-synuclein
    DOI:  https://doi.org/10.1177/10915818251378724
  15. PLoS One. 2025 ;20(9): e0331024
    Antibodies raised against a structurally defined Aβ oligomer mimic protect human iPSC neurons from Aβ toxicity at sub-stoichiometric concentrations.
    Sarah M Ruttenberg, Rakia Dhaoui, Adam G Kreutzer, James S Nowick.
      Anti-Aβ antibodies are important tools for identifying structural features of aggregates of the Aβ peptide and are used in many aspects of Alzheimer's disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb2AT-L, that is moderately selective for oligomeric Aβ over monomeric and fibrillar Aβ and recognizes the diffuse peripheries of Aβ plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined Aβ oligomer mimic composed of three Aβ-derived β-hairpins arranged in a triangular fashion and covalently stabilized with three disulfide bonds. In the current study, we set out to determine if pAb2AT-L is neuroprotective against toxic aggregates of Aβ and found that pAb2AT-L protects human iPSC-derived neurons from Aβ42-mediated toxicity at molar ratios as low as 1:100 antibody to Aβ42, with a ratio of 1:25 almost completely rescuing cell viability. Few other antibodies have been reported to exhibit neuroprotective effects at such low ratios of antibody to Aβ. ThT and TEM studies indicate that pAb2AT-L delays but does not completely inhibit Aβ42 fibrillization at sub-stoichiometric ratios. The ability of pAb2AT-L to inhibit Aβ42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb2AT-L binds toxic Aβ42 oligomers and does not simply sequester monomeric Aβ42. These results further suggest that toxic oligomers of Aβ42 share significant structural similarities with 2AT-L.
    DOI:  https://doi.org/10.1371/journal.pone.0331024
  16. Cells. 2025 Sep 02. pii: 1370. [Epub ahead of print]14(17):
    Deficiency of N1-Adenine Methyltransferase Aggravates RNA and Protein Aggregation.
    Marion Alriquet, Roberto Arsiè, Giulia Calloni, Gian G Tartaglia, R Martin Vabulas.
      RNA modifications regulate diverse aspects of transcripts' function and stability. Among these, N1-methyladenine (m1A) is a reversible mark primarily installed by the TRMT6/TRMT61A methyltransferase on tRNA, though it is also found on other RNA types. m1A has been implicated in protecting mRNAs during acute protein misfolding stress. However, the role of m1A under chronic proteotoxic conditions, such as intracellular amyloid aggregation, remains poorly understood. To address this gap, we examined the effects of reduced N1-adenine methylation in human cells undergoing amyloidogenesis. Suppression of the methyltransferase TRMT61A or overexpression of the m1A-specific demethylase ALKBH3 enhanced amyloid aggregation. A deficiency of N1-adenine methylation also impaired the expression of a reporter mRNA-encoded protein, highlighting the protective role of m1A in safeguarding transcript functionality. Proteomic analysis of amyloid aggregates from TRMT61A-deficient cells revealed increased co-aggregation of bystander proteins, particularly those with known RNA-binding activity. At the same time, the aggregates from methylation-deficient cells contained elevated levels of mRNAs. Collectively, our findings support a role for m1A in preventing RNA entanglement within aggregates and limiting RNA-mediated propagation of protein co-aggregation.
    Keywords:  N1-methyladenine; RBP; TRMT6/TRMT61A; protein aggregation
    DOI:  https://doi.org/10.3390/cells14171370
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