bims-proned 2025-05-18 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–05–18
sixteen papers selected by
Verena Kohler, Umeå University

Endocytic Pathways Unveil the Role of Syndecans in the Seeding and Spreading of Pathological Protein Aggregates: Insights into Neurodegenerative Disorders.
Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils.
Heterotypic Droplet Formation by Pro-Inflammatory S100A9 and Neurodegenerative Disease-Related α-Synuclein.
Modulation of insulin aggregation by betaine and proline directly observed via real-time super-resolution microscopy.
Chronic Vanadium Exposure Promotes Aggregation of Alpha-Synuclein, Tau and Amyloid Beta in Mouse Brain.
Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration.
Chiral Carbon Nanodots Modulate α-Synuclein Homeostasis to Combat Parkinson's Disease.
Macrophages in the dCLN are required for α-synuclein proteostasis in A53T PD model mice.
Stress granules: emerging players in neurodegenerative diseases.
Fine-Tuning Ferroptosis by Modulating GPX4 and Its Potential in Mitigating Neuronal Degeneration in Parkinson's Disease.
Optimization of a High-Throughput Screen for Monitoring Disease-Associated Protein Misfolding and Aggregation in Bacteria.
An approach to characterize mechanisms of action of anti-amyloidogenic compounds in vitro and in situ.
NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.
Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival.
Liquid-liquid phase separation of Tau and α-synuclein: a new target for treating comorbidity in neurodegeneration.
GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer's Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation.

Int J Mol Sci. 2025 Apr 24. pii: 4037. [Epub ahead of print]26(9):

Endocytic Pathways Unveil the Role of Syndecans in the Seeding and Spreading of Pathological Protein Aggregates: Insights into Neurodegenerative Disorders.

Anett Hudák, Tamás Letoha.

  Alzheimer's disease and other neurodegenerative disorders are characterized by the accumulation of misfolded proteins, such as amyloid-beta, tau, and α-synuclein, which disrupt neuronal function and contribute to cognitive decline. Heparan sulfate proteoglycans, particularly syndecans, play a pivotal role in the seeding, aggregation, and spreading of toxic protein aggregates through endocytic pathways. Among these, syndecan-3 is particularly critical in regulating the internalization of misfolded proteins, facilitating their propagation in a prion-like manner. This review examines the mechanisms by which syndecans, especially SDC3, contribute to the seeding and spreading of pathological protein aggregates in neurodegenerative diseases. Understanding these endocytic pathways provides valuable insights into the potential of syndecans as biomarkers and therapeutic targets for early intervention in Alzheimer's disease and other related neurodegenerative disorders.

Keywords:  endocytosis; heparan sulfate proteoglycans; neurodegeneration; protein aggregation; syndecans

DOI:  https://doi.org/10.3390/ijms26094037
Protein Sci. 2025 Jun;34(6): e70150

Using a stable protein scaffold to display peptides that bind to alpha-synuclein fibrils.

Samuel Bismut, Matthias M Schneider, Masashi Miyasaki, Yuqing Feng, Ellis J Wilde, M Dylan Gunawardena, Tuomas P J Knowles, Gabrielle S Kaminski Schierle, Laura S Itzhaki, Janet R Kumita.

  Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

Keywords:  amyloid fibrils; fibril‐binders; protein scaffolds; α‐synuclein

DOI:  https://doi.org/10.1002/pro.70150
Biomacromolecules. 2025 May 15.

Heterotypic Droplet Formation by Pro-Inflammatory S100A9 and Neurodegenerative Disease-Related α-Synuclein.

Dominykas Veiveris, Aurimas Kopustas, Darius Sulskis, Kamile Mikalauskaite, Mohammad Nour Alsamsam, Marijonas Tutkus, Vytautas Smirnovas, Mantas Ziaunys.

Liquid-liquid phase separation of proteins and nucleic acids is a rapidly emerging field of study, aimed at understanding the process of biomolecular condensate formation. Recently, it has been discovered that different neurodegenerative disease-related proteins, such as α-synuclein and amyloid-β are capable of forming heterotypic droplets. Other reports have also shown non-LLPS cross-interactions between various amyloidogenic proteins and the resulting influence on their amyloid fibril formation. This includes the new discovery of pro-inflammatory S100A9 affecting the aggregation of both amyloid-β, as well as α-synuclein. In this study, we explore the formation of heterotypic droplets by S100A9 and α-synuclein. We show that their mixture is capable of assembling into both homotypic and heterotypic condensates and that this cross-interaction alters the aggregation mechanism of α-synuclein. These results provide insight into the influence of S100A9 on the process of neurodegenerative disease-related protein LLPS and aggregation.

DOI: https://doi.org/10.1021/acs.biomac.5c00130
Protein Sci. 2025 Jun;34(6): e70149

Modulation of insulin aggregation by betaine and proline directly observed via real-time super-resolution microscopy.

Steen W B Bender, Jacob Kæstel-Hansen, Vito Foderà, Nikos S Hatzakis, Min Zhang.

  Protein aggregation is associated with a spectrum of neurodegenerative diseases. Although many small ligands have been found to modulate or inhibit protein aggregation, their molecular mechanisms remain unclear. One reason for this is the inherent heterogeneity of protein aggregation pathways with different kinetics that result in the coexistence of multiple structures, for example, protein spherulites and fibrils, challenging the analysis of protein-ligand interactions. To address this issue, we evaluated the roles of betaine and proline in insulin aggregation. We employed our recently developed super-resolution microscopy real-time kinetics via binding and photobleaching localization microscopy (REPLOM) to directly observe the formation and morphological evolution of individual insulin aggregates in real time, with or without betaine/proline. Utilizing our machine learning approach, we monitor the effect of betaine and proline on the aggregation pathways and extract the growth kinetics of each individual aggregate type. Our results show that a high concentration of betaine or proline modulates the heterogeneity of the final aggregates, leading to the formation of smaller aggregates in a mixture with spherulites. The fraction of small aggregates increases with betaine/proline concentration, highlighting the heterogeneity of protein aggregation, and our toolbox can unravel the effects of small molecule ligands on individual protein aggregation pathways and the resulting aggregate types and abundances.

Keywords:  REPLOM; modulation; protein aggregation; real‐time direct observation; super‐resolution microscopy

DOI:  https://doi.org/10.1002/pro.70149
J Neurochem. 2025 May;169(5): e70082

Chronic Vanadium Exposure Promotes Aggregation of Alpha-Synuclein, Tau and Amyloid Beta in Mouse Brain.

O R Folarin, F E Olopade, T T Gilbert, A D Ladagu, P I Pires Dos Santos, O A Mustapha, L Z Kpasham, J O Olopade, T F Outeiro.

  The interaction of toxic environmental metals and metalloids with brain proteins and polypeptides can result in pathological aggregations and formation of toxic oligomers, which are key features of many neurodegenerative diseases. Occupational and environmental exposure to vanadium is connected to a neurological syndrome that includes psychiatric symptoms, cognitive decline, and neurodegeneration. In this study, we hypothesized that prolonged vanadium exposure may be a potential risk factor for Alzheimer's and Parkinson's diseases. A total of 72 male BALB/c mice, each 4 weeks' old, were used. Vanadium-treated groups received intraperitoneal injections of 3 mg/kg body weight of vanadium three times a week for 6, 12, or 18 months. The control group received sterile water while the withdrawal group were given vanadium injection for 3 months, followed by withdrawal of the metal, but treatment with sterile water only, and were sacrificed at 3-, 9-, or 15-months post vanadium exposure. Sagittal sections of brain paraffin-embedded tissue were prepared and analyzed using immunofluorescence to study the immunoreactivity and cellular localization of α-synuclein (α-syn), amyloid-β (Aβ), and tau proteins. Our findings revealed pathological aggregation of these proteins in the frontoparietal cortices and the dorsal CA1 and CA3 regions. Double immunolabeling with glial cells and neurons showed neuronal degeneration, functional gliosis, and activation of astrocytes and microglia at sites of α-synuclein immunoreactivity. We observed increased immunoreactivity of phosphorylated nuclei tau both in the parietal cortices and corpus callosum white matter while we observed intraneuronal accumulation of Aβ deposits in the cortex and dorsal hippocampal regions in vanadium treated brains. These cellular changes and proteinopathies, although persisting, were significantly attenuated after vanadium withdrawal. Our findings show that prolonged vanadium exposure promotes abnormal accumulation of neurodegeneration-associated proteins (α-syn, Tau, and Aβ) in the brain, which is further exacerbated by aging in the context of extended exposure to the metal.

Keywords:  aging; neurodegeneration; protein aggregation; proteinopathies; vanadium

DOI:  https://doi.org/10.1111/jnc.70082
Aging Cell. 2025 May 16. e70091

Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration.

Jonathan Plessis-Belair, Taylor Russo, Markus Riessland, Roger B Sher.

  Neurodegenerative diseases (NDDs) and other age-related disorders have been classically defined by a set of key pathological hallmarks. Two of these hallmarks, cell cycle dysregulation (CCD) and nucleocytoplasmic transport (NCT) defects, have long been debated as being either causal or consequential in the pathology of accelerated aging. Specifically, aberrant cell cycle activation in post-mitotic neurons has been shown to trigger neuronal cell death pathways and cellular senescence. Additionally, NCT has been observed to be progressively dysregulated during aging and in neurodegeneration, where the increased subcellular redistribution of nuclear proteins, such as TAR DNA-Binding Protein-43 (TDP-43), to the cytoplasm is a primary driver of disease. However, the functional significance of NCT defects as either a causal mechanism or consequence of pathology, and how the redistribution of cell cycle machinery contributes to neurodegeneration, remains unclear. Here, we describe that pharmacological inhibition of importin-β nuclear import is capable of perturbing cell cycle machinery both in mitotic neuronal cell lines and post-mitotic primary neurons in vitro. Our NemfR86S mouse model of motor neuron disease, characterized by nuclear import defects, further recapitulates the hallmarks of CCD we observed in mitotic cell lines and in post-mitotic primary neurons in vitro, and in spinal motor neurons in vivo. The observed CCD is consistent with the transcriptional and phenotypical dysregulation commonly associated with neuronal cell death and senescence-like features in NDDs. Together, this evidence suggests that impairment of nuclear import pathways resulting in CCD may be a common driver of pathology in neurodegeneration.

Keywords:  cell cycle; neurodegeneration; nuclear import

DOI:  https://doi.org/10.1111/acel.70091
Small Methods. 2025 May 15. e2500557

Chiral Carbon Nanodots Modulate α-Synuclein Homeostasis to Combat Parkinson's Disease.

Yurong Han, Yuqi Zhang, Jiahao Huang, Xiaodan Jia, Taka-Aki Ishibashi, Xiue Jiang.

  Inhibiting α-synuclein (α-syn) aggregation is an effective treatment for Parkinson's disease (PD), and chiral recognition of proteins offers a novel strategy for designing efficient inhibitors. However, the impact of chiral selectivity on α-syn aggregation and its regulatory mechanisms remain ambiguous. In this work, it is synthesized chiral carbon nanodots (CNDs), including L-CNDs, D-CNDs, and DL-CNDs, and found that D-CNDs exhibited the most potent inhibitory effect on α-syn aggregation. ¹H-¹⁵N heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy revealed that CNDs primarily interact with α-syn through electrostatic interactions, with D-CNDs specifically targeting key aggregation-prone residues, thereby disrupting β-sheet formation and reducing fibril assembly. In contrast, L-CNDs and DL-CNDs exhibited limited inhibitory effects, attributed to their weak affinity for the non-amyloid-β component region. Moreover, CNDs efficiently crossed the blood-brain barrier, and D-CNDs significantly reduced α-syn accumulation, alleviated neuronal damage, and ameliorated cognitive function. This work underlines the critical role of chirality in modulating α-syn aggregation and provides a novel strategy for developing enantiomer-selective inhibitors for PD therapy.

Keywords:  Parkinson's disease; chiral carbon nanodots; inhibition of aggregation; protein folding; α‐synuclein

DOI:  https://doi.org/10.1002/smtd.202500557
Brain Res. 2025 May 10. pii: S0006-8993(25)00251-3. [Epub ahead of print]1860 149692

Macrophages in the dCLN are required for α-synuclein proteostasis in A53T PD model mice.

Luzheng Xu, Jingcheng Deng, Wei Xiong, Li Li, Zongran Liu.

  The metabolic disorder of α-synuclein in the central nervous system (CNS) is a key factor leading to excessive accumulation of aggregated α-synuclein and ultimately to the formation of Lewy bodies, which is one of the main pathological features of Parkinson's disease (PD). Although the mechanism underlying this process remains elusive, systemic metabolic abnormalities have been demonstrated to affect the progression of neurodegenerative diseases. The recent discovery of meningeal lymphatics provides a specific route for connection between the CNS and the periphery. As draining lymph nodes for CSF, the deep cervical lymph nodes (dCLN) are important for maintaining CNS homeostasis. However, whether and how macrophages in the peripheral dCLN system are involved in the α-synuclein homeostasis is largely unknown. Here, we report that macrophages in the deep cervical lymph node (dCLN) are required for maintaining α-synuclein proteostasis in an LRRK2 and lysosome-dependent pathway in A53T PD model mice, providing a fresh perspective on understanding the pathology of PD.

Keywords:  LRRK2; Lymphatic drainage; Macrophage; Parkinson’s disease; α-synuclein

DOI:  https://doi.org/10.1016/j.brainres.2025.149692
Transl Neurodegener. 2025 May 12. 14(1): 22

Stress granules: emerging players in neurodegenerative diseases.

Lin Yuan, Li-Hong Mao, Yong-Ye Huang, Tiago F Outeiro, Wen Li, Tuane C R G Vieira, Jia-Yi Li.

  Stress granules (SGs) are membraneless organelles formed in the cellular cytoplasm under stressful conditions through liquid-liquid phase separation (LLPS). SG assembly can be both dependent and independent of the eIF2α pathway, whereas cellular protein quality control systems mediate SG disassembly. Chaperones and specific domains of RNA-binding proteins strongly contribute to the regulation SG dynamics. Chronic stress, arising in association with aging, may promote persistent SGs that are difficult to disassemble, thereby acting as a potential pathological nidus for protein aggregation in neurodegenerative diseases (NDDs). In this review, we discuss the dynamics of SGs and the factors involved with SG assembly and disassembly. We also highlight the relationship among LLPS, SGs, and the pathogenesis of different NDDs. More importantly, we summarize SG assembly-disassembly, which may be a double-edged sword in the pathophysiology of NDDs. This review aims to provide new insights into the biology and pathology of LLPS, SGs, and NDDs.

Keywords:  Liquid–liquid phase separation; Neurodegenerative disease; RNA-binding protein; Stress granules

DOI:  https://doi.org/10.1186/s40035-025-00482-9
Chembiochem. 2025 May 05. 26(9): e202401052

Fine-Tuning Ferroptosis by Modulating GPX4 and Its Potential in Mitigating Neuronal Degeneration in Parkinson's Disease.

Michael M Shahid, Grace Hohman, Mohamed Eldeeb.

  The increasing prevalence of neurodegenerative diseases necessitates the development of novel approaches to study, diagnose, and treat these devastating disorders. Accordingly, there is a critical need to precisely address the gap in the biochemical and physiological mechanisms that underlie neurodegenerative diseases to promote advancements in therapeutic interventions. Parkinson's Disease (PD), the second most common neurodegenerative disorder after Alzheimer's, demands further research focused on unravelling the rather intricate molecular mechanisms that drive its progression upon different cell signaling cues. While alpha-synuclein aggregation and mitochondrial dysfunction are two cellular hallmarks of the molecular pathophysiology of PD, few drugs are currently in clinical trials for treatment of PD, which warrants further studies to identify new therapeutic molecular targets. Herein, we briefly highlight some of the reported roles of ferroptosis, a modality of cell death that is driven by iron-dependent phospholipid peroxidation, and its regulation by glutathione peroxidase 4 (GPX4). We discuss the interconnectedness between lipid peroxidation and GPX4 regulation in the context of molecular pathogenesis of PD. Future studies are imperative in investigating the physiological role of ferroptosis and the translational impact of ferroptosis-specific modulators in studying PD biology.

Keywords:  Ferroptosis; Parkinson's disease; Protein degradation; glutathione peroxidase 4; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1002/cbic.202401052
ACS Synth Biol. 2025 May 12.

Optimization of a High-Throughput Screen for Monitoring Disease-Associated Protein Misfolding and Aggregation in Bacteria.

Dafni C Delivoria, Eleni Konia, Ilias Matis, Georgios Skretas.

  Protein misfolding and aggregation are central features of a wide range of diseases, including neurodegenerative disorders, systemic amyloidoses, and cancer. The identification of compounds that can modulate protein folding and aggregation is a key step toward developing effective therapies. High-throughput screening methods are essential for efficiently identifying such compounds. In this study, we optimized a previously developed high-throughput genetic screen for monitoring protein misfolding and aggregation in bacteria. This system is based on monitoring the fluorescence of Escherichia coli cells expressing fusions of human misfolding-prone and disease-related proteins (MisPs) with the green fluorescent protein. We systematically tested a variety of experimental conditions, such as overexpression conditions and MisP-GFP fusion formats, to identify key parameters that affect the sensitivity and dynamic range of the assay. Using misfolding-prone, cancer-associated variants of human p53 as a model system, we found that strong overexpression conditions, such as high copy number vectors, strong promoters, high inducer concentrations, and high overexpression temperatures, can yield optimal assay performance. These optimized assay conditions were also validated with additional MisPs, such as the Alzheimer's disease-associated amyloid-β peptide and variants of superoxide dismutase 1 associated with amyotrophic lateral sclerosis. At the same time, we observed that certain conditions, such as inducer concentrations and overexpression temperature, may need to be precisely fine-tuned for each new MisP target to yield optimal assay performance. Our findings provide a framework for standardizing MisP-GFP screening assays, facilitating their broad application in the discovery of therapeutic agents targeting protein misfolding and aggregation.

Keywords:  SOD1; amyloid β; green fluorescent protein; high-throughput screening; p53; protein aggregation; protein misfolding diseases

DOI:  https://doi.org/10.1021/acssynbio.5c00166
NPJ Parkinsons Dis. 2025 May 10. 11(1): 122

An approach to characterize mechanisms of action of anti-amyloidogenic compounds in vitro and in situ.

P Stalder, T Serdiuk, D Ghosh, Y Fleischmann, N Ait-Bouziad, J-P Quast, L Malinovska, A Ouared, A Davranche, W Haenseler, C Boudou, E Tsika, J Stöhr, R Melki, R Riek, N de Souza, P Picotti.

Amyloid aggregation is associated with neurodegenerative disease and its modulation is a focus of drug development. We developed a chemical proteomics pipeline to probe the mechanism of action of anti-amyloidogenic compounds. Our approach identifies putative interaction sites with high resolution, can probe compound interactions with specific target conformations and directly in cell and brain extracts, and identifies off-targets. We analysed interactions of six anti-amyloidogenic compounds and the amyloid binder Thioflavin T with different conformations of the Parkinson's disease protein α-Synuclein and tested specific compounds in cell or brain lysates. AC Immune compound 2 interacted with α-Synuclein in vitro, in intact neurons and in neuronal lysates, reduced neuronal α-Synuclein levels in a seeded model, and had protective effects. EGCG, Baicalein, ThT and doxycycline interacted with α-Synuclein in vitro but not substantially in cell lysates, with many additional putative targets, underscoring the importance of testing compounds in situ. Our pipeline will enable screening of compounds against any amyloidogenic proteins in cell and patient brain extracts and mechanistic studies of compound action.

DOI: https://doi.org/10.1038/s41531-025-00966-5
Front Mol Neurosci. 2025 ;18 1551571

NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.

Hossein Khodadadi, Kamila Łuczyńska, Dawid Winiarczyk, Paweł Leszczyński, Hiroaki Taniguchi.

  Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Nuclear Factor Erythroid 2-Related Factor 1 (NFE2L1) has emerged as a key regulator of proteostasis, integrating proteasome function, autophagy, and ferroptosis to counteract oxidative stress and protein misfolding. This review synthesizes current knowledge on the role of NFE2L1 in maintaining neuronal homeostasis, focusing on its mechanisms for mitigating proteotoxic stress and supporting cellular health, offering protection against neurodegeneration. Furthermore, we discuss the pathological implications of NFE2L1 dysfunction and explore its potential as a therapeutic target. By highlighting gaps in the current understanding and presenting future research directions, this review aims to elucidate NFE2L1's role in advancing treatment strategies for neurodegenerative diseases.

Keywords:  NFE2L1; autophagy; ferroptosis; mitochondrial health; neurodegenerative diseases; oxidative stress; proteasome; proteostasis

DOI:  https://doi.org/10.3389/fnmol.2025.1551571
J Am Chem Soc. 2025 May 14.

Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival.

Zijun Gao, Ruomeng Qiu, Dhwanit R Dave, Palash Chandravanshi, Gisele P Soares, Cara S Smith, J Alberto Ortega, Liam C Palmer, Zaida Álvarez, Samuel I Stupp.

Neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.

DOI: https://doi.org/10.1021/jacs.5c00105
Biophys Rev. 2025 Apr;17(2): 491-498

Liquid-liquid phase separation of Tau and α-synuclein: a new target for treating comorbidity in neurodegeneration.

Nahuel N Foressi, Leandro Cruz Rodríguez, M Soledad Celej.

  Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders, causing significant disability and mortality worldwide. Though traditionally classified as Tau and α-synuclein-related disorders, respectively, there is growing evidence of clinical overlap between dementia and Parkinsonism, with comorbidity worsening cognitive impairment and prognosis. Emerging research on liquid-liquid phase separation (LLPS) offers promising insights into novel treatments of these proteinopathies by targeting the phase behavior of the disease-associated proteins. Thus, manipulating condensates has become a focus for developing new therapeutic compounds, termed condensate-modifying drugs (c-mods), by which historically considered undruggable proteins can be targeted. This review offers an overview of bioactive molecules that act as modifiers of Tau and α-synuclein condensates through various mechanisms. The goal is to lay the groundwork for discovering new therapeutic approaches to prevent harmful protein aggregation and treat comorbidity in tau and synucleinopathies.

Keywords:  Alzheimer; Amyloid; C-mods; Condensates; Parkinson; Phase separation

DOI:  https://doi.org/10.1007/s12551-024-01259-6
Int J Mol Sci. 2025 Apr 28. pii: 4167. [Epub ahead of print]26(9):

GAL-201 as a Promising Amyloid-β-Targeting Small-Molecule Approach for Alzheimer's Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation.

Katrin Riemann, Jeldrik von Ahsen, Tamara Böhm, Martin Schlegel, Matthias Kreuzer, Thomas Fenzl, Hermann Russ, Christopher G Parsons, Gerhard Rammes.

  Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer's disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ1-42, Aβ(p3-42), Aβ1-40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ1-42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the "tgArcSwe" AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD.

Keywords:  3NTyr(10)-Aβ); Alzheimer’s disease; Aβ(p3-42); Aβ1–40; activation of microglia and astrocytes; amyloid-β-aggregation-inhibitor; amyloid-β-induced spine loss; modulation of amyloid-β-aggregation; neurodegenerative diseases; neuroinflammation; neuroprotection; off-pathway aggregation; prion-like mechanism; small molecule; synaptic plasticity; tgArcSwe mice; toxic oligomers

DOI:  https://doi.org/10.3390/ijms26094167