bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–05–04
nineteen papers selected by
Verena Kohler, Umeå University
  1. The Role of α-Synuclein-DNAJB6b Coaggregation in Amyloid Suppression.
  2. Plant-Based Inhibitors of Protein Aggregation.
  3. Trehalose-releasing nanogels reduce α-synuclein-induced Lewy body-like inclusions in primary mouse hippocampal neurons.
  4. The interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression.
  5. Paraquat exposure triggers amyloid-β and α-synuclein aggregation in the prefrontal cortex of mice: Suppression of microglial phagocytosis via IL-17A.
  6. A triosmium carbonyl cluster that inhibits α-synuclein aggregation and disassembles preformed aggregates.
  7. Criterion for Assessing Accumulated Neurotoxicity of Alpha-Synuclein Oligomers in Parkinson's Disease.
  8. α-Synuclein condensation in synaptic vesicle function and synucleinopathies.
  9. Inhibition of cytotoxic fibril formation of α-synuclein and human insulin by Silymarin from the Silybum marianum.
  10. The hidden costs of imperfection: transcription errors in protein aggregation diseases.
  11. An Insight into Neuronal Processing of Ghrelin: Effects of a Bioactive Ghrelin Derivative on Proteolytic Pathways and Mitophagy.
  12. Lactoferrin as a Candidate Multifunctional Therapeutic in Synucleinopathies.
  13. Binding of Hg(I) and Hg(II) Ions to Amyloid-Beta (Aβ) Peptide Variants Affect Their Structure and Aggregation.
  14. Regulation of misfolded protein aggregation and degradation by SUMOylation in budding yeast.
  15. Repurposing major metabolites of lamiaceae family as potential inhibitors of α-synuclein aggregation to alleviate neurodegenerative diseases: an in silico approach.
  16. Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.
  17. Massive experimental quantification allows interpretable deep learning of protein aggregation.
  18. Truncation mutation of CHMP2B disrupts late endosome function but reduces TDP-43 aggregation through HSP70 upregulation.
  19. Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds.
  1. ACS Chem Neurosci. 2025 Apr 30.
    The Role of α-Synuclein-DNAJB6b Coaggregation in Amyloid Suppression.
    Tinna Pálmadóttir, Josef Getachew, Dev Thacker, Johan Wallerstein, Ulf Olsson, Cecilia Emanuelsson, Sara Linse.
      Chaperones may retard the aggregation of other proteins and increase their solubility. An important goal is a thermodynamic understanding of such an action. Here, the chaperone DNAJB6b (JB6) is found to suppress amyloid formation of the protein α-synuclein (α-syn) leading to a reduced rate of fibril formation and an increase in apparent solubility of α-syn. These findings were reached at mildly acidic pH and with light seeding under conditions where the effect on secondary nucleation is visible. Cryo-transmission electron microscopy (cryo-TEM) imaging reveals that coaggregates of α-syn and JB6 are formed with significantly altered ultrastructure compared to both pure protein fibrils and pure chaperone aggregates. This is further supported by the formation of ThT-negative aggregates and by the depletion of JB6 from solution in the presence of α-syn. The identification of such coaggregates provides a plausible thermodynamic explanation for an increase in α-syn solubility in the presence of JB6; the reduced chemical potential of the chaperone upon formation of coaggregates can compensate for an increased chemical potential of α-syn, and the system as a whole can lower its free energy to sustain an increased free α-syn concentration.
    Keywords:  aggregation equilibrium; aggregation rate; chaperone action; coaggregation; self-assembly; solubility enhancement
    DOI:  https://doi.org/10.1021/acschemneuro.4c00883
  2. Biomolecules. 2025 Mar 25. pii: 481. [Epub ahead of print]15(4):
    Plant-Based Inhibitors of Protein Aggregation.
    Olha Zhytniakivska, Tanmay Chaturvedi, Mette Hedegaard Thomsen.
      The assembly of amyloidogenic proteins and peptides into toxic oligomeric and fibrillar aggregates is closely connected to the onset and progression of more than 50 protein diseases, such as Alzheimer's disease, Parkinson's disease, prion disease, and type 2 diabetes, to name only a few. Considerable research efforts at identifying the therapeutic strategies against these maladies are currently focused on preventing and inhibiting pathogenic protein aggregation by various agents. Plant-based extracts and compounds have emerged as promising sources of potential inhibitors due to their dual role as nutraceuticals as part of healthy diets and as specific pharmaceuticals when administered at higher concentrations. In recent decades, several plant extracts and plant-extracted compounds have shown potential to modulate protein aggregation. An ever-growing body of research on plant-based amyloid inhibitors requires a detail analysis of existing data to identify potential knowledge gaps. This review summarizes the recent progress in amyloid inhibition using 17 flavonoids, 11 polyphenolic non-flavonoid compounds, 23 non-phenolic inhibitors, and 59 plant extracts, with the main emphasis on directly modulating the fibrillation of four amyloid proteins, namely amyloid-β peptide, microtubule-associated protein tau, α-synuclein, and human islet amyloid polypeptide.
    Keywords:  amyloid fibrils; plant-extracted compounds; protein misfolding
    DOI:  https://doi.org/10.3390/biom15040481
  3. J Mater Chem B. 2025 Apr 28.
    Trehalose-releasing nanogels reduce α-synuclein-induced Lewy body-like inclusions in primary mouse hippocampal neurons.
    Ali Maruf, Dmytro Gerasymchuk, Irena Hlushchuk, Safak Er, Małgorzata Milewska, Piotr Chmielarz, Andrii Domanskyi, Mikko Airavaara, Ilona Wandzik.
      Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, clinically characterized by both motor and non-motor symptoms. A key hallmark of PD is the accumulation of misfolded α-synuclein, which aggregates to Lewy bodies (LB) formed inside neurons. Trehalose, a disaccharide that induces autophagy, has been demonstrated to reduce α-synuclein aggregation in vivo. However, the enzyme trehalase rapidly degrades free trehalose, and its hydrophilicity causes poor penetration through the cell membrane. Thus, advanced trehalose delivery strategies are urgently needed. Herein, we investigated the effects of trehalose-bearing nanogels for reducing α-synuclein protein-induced perinuclear LB-like pathology in primary mouse hippocampal neurons. The study compares the effects of trehalose-releasing nanogel (TR) and trehalose-non releasing nanogel (TNR). The results showed that TR, but not TNR, nor free trehalose reduced LB-like inclusions in primary hippocampal neurons. The neuroprotective effects of TR may result from the synergistic effects of direct limitation of α-synuclein aggregates formation and trehalose release-induced autophagy promoting aggregates clearance. Overall, enhancing trehalose delivery with nanogels that can sustainably release trehalose could be worth further investigation as a new potential option for reducing α-synuclein aggregation in neurons affected by neurodegenerative diseases.
    DOI:  https://doi.org/10.1039/d4tb02704c
  4. Mol Med. 2025 Apr 26. 31(1): 154
    The interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression.
    Yan Chen, Xixi Luo, Yukun Yin, Elizabeth Rosalind Thomas, Kezhi Liu, Wenjun Wang, Xiang Li.
      The irreversible degeneration of dopamine neurons induced by α-synuclein (α-syn) aggregation in the substantia nigra is the central pathological feature of Parkinson's disease (PD). Neuroimaging and pathological autopsy studies consistently confirm significant iron accumulation in the brain of PD patients, suggesting a critical role for iron in disease progression. Current research has established that iron overload induces ferroptosis in dopaminergic neurons, evidence indicates that the impact of iron on PD pathology extends beyond ferroptosis. Iron also plays a regulatory role in modulating α-syn, affecting its aggregation, spatial conformation, post-translational modifications, and mRNA stability. Iron-induced α-syn aggregation can contribute to dopaminergic neurodegeneration through additional mechanisms, potentially creating a feedback loop in which α-syn further enhances iron accumulation, thus perpetuating a vicious cycle of neurotoxicity. Given α-syn's intrinsically disordered structure, targeting iron metabolism presents a promising therapeutic strategy for PD. Therefore, the development of iron chelators, alone or in combination with other therapeutic drugs, may offer a beneficial approach to alleviating PD symptoms and slowing disease progression.
    Keywords:  Ferroptosis; Iron; Parkinson's disease; α-synuclein
    DOI:  https://doi.org/10.1186/s10020-025-01208-3
  5. Int Immunopharmacol. 2025 Apr 28. pii: S1567-5769(25)00736-2. [Epub ahead of print]157 114746
    Paraquat exposure triggers amyloid-β and α-synuclein aggregation in the prefrontal cortex of mice: Suppression of microglial phagocytosis via IL-17A.
    Rong Hu, Ge Shi, Chenyang Wu, Yuxuan Jiao, Yonghang Li, Ai Qi, Yujing Li, Qianrong Zhang, Qi Liu, Kaidong Wang, Min Huang.
      Paraquat (PQ), an environmental neurotoxin, has been demonstrated to induce pathological protein aggregation and thus neurotoxicity. Nevertheless, the exact mechanisms remain elusive. In this investigation, we explored the involvement of interleukin-17A (IL-17 A) in the aggregation of amyloid-β (Aβ) and α-synuclein (α-syn) induced by PQ. Combining in vitro and in vivo, we explored whether PQ leads to Aβ and α-syn aggregation through IL-17 A-mediated reduction in microglia phagocytosis, thereby aggravating neurotoxicity. The results demonstrated that low-dose PQ continuous exposure significantly elevated IL-17 A levels in the peripheral blood serum and prefrontal cortical regions of mice. It also suppressed microglial phagocytosis of pathological proteins and promoted the aggregation of Aβ and α-syn in the prefrontal cortex. These changes ultimately resulted in depression, anxiety, and cognitive impairments. Mechanistically, IL-17 A inhibited the expression of the microglial phagocytic receptor CD36, impairing the microglial ability to clear Aβ and α-syn. Furthermore, administering an anti-IL-17 A effectively restored microglial phagocytosis in PQ-exposed mice, reduced Aβ and α-syn aggregation in prefrontal cortical areas, and alleviated behavioral deficits. In conclusion, this paper highlights IL-17 A as a pivotal mediator in PQ-induced neurotoxicity. It provides a potential target for developing novel therapeutic strategies against neurodegenerative pathologies induced by such environmental toxicants.
    Keywords:  Amyloid-β; CD36; IL-17A; Microglial phagocytosis; Paraquat; α-Synuclein
    DOI:  https://doi.org/10.1016/j.intimp.2025.114746
  6. Chem Commun (Camb). 2025 Apr 28.
    A triosmium carbonyl cluster that inhibits α-synuclein aggregation and disassembles preformed aggregates.
    Xin Liang, Balasz Gulyas, Mathangi Palanivel, Weng Kee Leong.
      Two triosmium carbonyl clusters, viz., Os3(μ-H)(μ-SC6H4-p-NO2)(CO)10 (1) and Os3(μ-H)(kO,μ-O'-2-flavone)(CO)9 (2), effectively inhibited α-synuclein aggregation, a key signature of Parkinson's disease (PD), in both wild-type and A53T-mutant α-synuclein models. Cluster 2 showed superior efficacy and a significantly better safety profile, and could also disassemble preformed aggregates.
    DOI:  https://doi.org/10.1039/d5cc01141h
  7. Int J Numer Method Biomed Eng. 2025 Apr;41(4): e70027
    Criterion for Assessing Accumulated Neurotoxicity of Alpha-Synuclein Oligomers in Parkinson's Disease.
    Andrey V Kuznetsov.
      The paper introduces a parameter called "accumulated neurotoxicity" of α-syn oligomers, which measures the cumulative damage these toxic species inflict on neurons over time, given the years it typically takes for such damage to manifest. A threshold value for accumulated neurotoxicity is estimated, beyond which neuron death is likely. Numerical results suggest that rapid deposition of α-syn oligomers into fibrils minimizes neurotoxicity, indicating that the formation of Lewy bodies might play a neuroprotective role. Strategies such as reducing α-syn monomer production or enhancing degradation can decrease accumulated neurotoxicity. In contrast, slower degradation (reflected by longer half-lives of monomers and free aggregates) increases neurotoxicity, supporting the idea that impaired protein degradation may contribute to Parkinson's disease progression. Accumulated neurotoxicity is highly sensitive to the half-deposition time of free α-syn aggregates into fibrils, exhibiting a sharp increase as it transitions from negligible to elevated levels, indicative of neural damage.
    Keywords:  Finke‐Watzky; Lewy body; mathematical modeling; neuron; α‐Synucleinopathy
    DOI:  https://doi.org/10.1002/cnm.70027
  8. Trends Cell Biol. 2025 Apr 29. pii: S0962-8924(25)00087-X. [Epub ahead of print]
    α-Synuclein condensation in synaptic vesicle function and synucleinopathies.
    Dan Li, Kaien Liu, Danni Li, Axel Brunger, Cong Li, Jacqueline Burré, Jiajie Diao.
      Research into the crosstalk between α-synuclein (α-syn) and synaptic vesicles (SVs) has gained considerable attention. Notably, the recently discovered liquid-liquid phase separation of α-syn involving SVs is crucial for performing their physiological functions and mediating the transition to pathological aggregates. This review first examines the functional interactions between α-syn and SVs in the context of α-syn's condensation state. It then explores how these interactions become disrupted under pathological conditions, leading to α-syn aggregation and subsequent synaptic dysfunction. Finally, the review discusses the therapeutic potential of targeting α-syn-SV interactions to restore synaptic function in diseased states. By connecting α-syn's physiological roles with its pathological effects, the article aims to shed light on its dual role as both a regulator of SVs and a driver of neurodegeneration.
    Keywords:  SNAREs; alpha-synuclein; phase separation; synaptic vesicles
    DOI:  https://doi.org/10.1016/j.tcb.2025.03.007
  9. PLoS One. 2025 ;20(5): e0320283
    Inhibition of cytotoxic fibril formation of α-synuclein and human insulin by Silymarin from the Silybum marianum.
    Beitollah Moosakhani, Mahshid Taleb, Zahra Mahmoudi Eshkaftaki, Nasser Nikfarjam, Azam Serajian, Mohammad Bagher Shahsavani, Ali Akbar Meratan.
      Silymarin (SIL), the extract obtained from the seeds of milk thistle (Silybum marianum), contains several flavonolignans with a broad range of therapeutic properties such as antioxidant, anti-inflammatory, and neuroprotective effects. Despite several studies indicating the neuroprotective effects of SIL in relating to neurodegenerative diseases (NDs), there is no report regarding the anti-amyloidogenic activity and the mechanism of action of SIL in vitro. Here, we have extracted SIL from the seeds of milk thistle (SIL A), followed by investigating its potential, in comparison with SIL purchased from Sigma company (SIL B), in modulating fibrillogenesis and cytotoxicity of human insulin and α-synuclein (α-syn) amyloid fibrils. The obtained results indicated the potency of both SIL A and SIL B in inhibiting the assembly process and related cytotoxicity of both proteins but via different mechanisms, including inhibition of amyloid fibrillation with the appearance of short fibrils for human insulin and redirecting the assembly process of α-syn toward the formation of small globular structures. The higher inhibitory effects of SIL B may be attributed to its higher silybin content, which is responsible for the most biological, including anti-amyloidogenic, activities of SIL B. Nanonization increased the capacity of both SILs to inhibit fibrillation and related cytotoxicity of both proteins. Taken together, these results may suggest SIL A as a potent candidate relating to NDs and highlight nanonization as a promising approach to increase its anti-amyloidogenic properties.
    DOI:  https://doi.org/10.1371/journal.pone.0320283
  10. Curr Opin Genet Dev. 2025 Apr 28. pii: S0959-437X(25)00042-5. [Epub ahead of print]93 102350
    The hidden costs of imperfection: transcription errors in protein aggregation diseases.
    Yingwo Sun, Marc Vermulst.
      At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer's and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.
    DOI:  https://doi.org/10.1016/j.gde.2025.102350
  11. Mol Neurobiol. 2025 Apr 26.
    An Insight into Neuronal Processing of Ghrelin: Effects of a Bioactive Ghrelin Derivative on Proteolytic Pathways and Mitophagy.
    Daniela Lufrano, Chunmei Gong, Valentina Cecarini, Massimiliano Cuccioloni, Laura Bonfili, Chiara Sturaro, Barbara Bettegazzi, Chiara Ruzza, Mario Perelló, Mauro Angeletti, Anna Maria Eleuteri.
      Protein homeostasis (proteostasis) is preserved by an orchestrated network of molecular mechanisms that regulate protein synthesis, folding, and degradation, ensuring cellular integrity and function. Proteostasis declines with age and is related to pathologies such as neurodegenerative diseases and cardiac disorders, which are accompanied by the accumulation of toxic protein aggregates. In this context, therapeutic strategies enhancing the two primary degradative systems involved in the cellular clearance of those abnormal proteins, namely ubiquitin-proteasome system and autophagy-lysosomal pathway, represent a promising approach to counteract the collapse of proteostasis in such pathological conditions. In this work, we explored the processing of ghrelin, a pleiotropic peptide hormone linked to energy metabolism and higher brain functions, which is reported to modulate the protein degradative mechanisms. According to our data, ghrelin is processed by serine hydrolases secreted into the conditioned medium of SH-SY5Y neuroblastoma cell line, commonly used in neurotoxicology and neuroscience research. Ghrelin processing leads to the formation of a shorter peptide (ghrelin(1-11)) that stimulates both the cell proteasome system and autophagy-lysosomal pathway, encompassing the selective autophagy of mitochondria. Our findings suggest that ghrelin processing may contribute to the maintenance of neuronal proteostasis.
    Keywords:  Autophagy; Ghrelin; Mitophagy; Neuronal Processing; Proteasome
    DOI:  https://doi.org/10.1007/s12035-025-04976-5
  12. Brain Sci. 2025 Apr 06. pii: 380. [Epub ahead of print]15(4):
    Lactoferrin as a Candidate Multifunctional Therapeutic in Synucleinopathies.
    Caroline A Barros, Tuane C R G Vieira.
      Lactoferrin (Lf) is a multifunctional glycoprotein with well-established antimicrobial, anti-inflammatory, and iron-binding properties. Emerging evidence suggests that Lf also plays a neuroprotective role, particularly in neurodegenerative disorders characterized by protein aggregation, such as Parkinson's disease (PD). Alpha-synuclein (aSyn) aggregation is a pathological hallmark of PD and other synucleinopathies, contributing to neuronal dysfunction and disease progression. Recent studies indicate that Lf may interfere with aSyn aggregation, iron chelation, and modulation of oxidative stress and neuroinflammation. Additionally, Lf's ability to cross the blood-brain barrier and its potential impact on the gut-brain axis highlight its promise as a therapeutic agent. This review explores Lf's mechanisms of action in synucleinopathies, its potential as a disease-modifying therapy, and innovative delivery strategies that could enhance its clinical applicability. By addressing the pathological and therapeutic dimensions of aSyn aggregation, we propose Lf as a compelling candidate for future research and clinical development in neurodegenerative diseases.
    Keywords:  Parkinson’s disease; aggregation; alpha-synuclein; lactoferrin; synucleophaties
    DOI:  https://doi.org/10.3390/brainsci15040380
  13. Chembiochem. 2025 Apr 30. e202500252
    Binding of Hg(I) and Hg(II) Ions to Amyloid-Beta (Aβ) Peptide Variants Affect Their Structure and Aggregation.
    Elina Berntsson, Andra Noormägi, Kärt Padari, Jüri Jarvet, Astrid Gräslund, Margus Pooga, Peep Palumaa, Sebastian K T S Wärmländer.
      Mercury (Hg) exposure is a possible risk factor for Alzheimer´s disease (AD). Some studies reported higher Hg levels in AD patients, but evidence is inconclusive. A mechanism linking Hg exposure to AD neuropathology remains to be found. The hallmark of AD brains is deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides.   Here, we use transmission electron microscopy (TEM) and biophysical spectroscopy techniques to study in vitro interactions between inorganic Hg and pathologically relevant Aβ(1-40) and Aβ(4-40) variants and the Aβ(1-40)(H6A, H13A, H14A) mutant. For the first time, effect on Aβ aggregation of both Hg(I) and Hg(II) is compared.   Hg(II) binds Aβ(1-40) with apparent binding affinity of 28±8 µM, at 20 °C in 20 mM MES buffer, pH 7.3. The N-terminal His6, His13 and His14 residues are involved in binding coordination. Hg(II) binding induces structural alterations (coil-coil interactions) in Aβ monomers positioned in membrane-mimicking SDS micelles. Equimolar amounts of either Hg(I) or Hg(II) inhibit normal Aβ fibrillation by directing aggregation towards formation of large amorphous aggregates. All these structural rearrangements may be relevant for the harmful Aβ aggregation processes involved in AD brain pathology. Inducing protein misfolding and aggregation might be a general toxic mechanism of mercury.
    Keywords:  Alzheimer's disease; Amyloid Aggregation; Heavy metal toxicity; Metal-protein binding; Neurodegeneration
    DOI:  https://doi.org/10.1002/cbic.202500252
  14. Mol Biol Cell. 2025 Apr 30. mbcE24120540
    Regulation of misfolded protein aggregation and degradation by SUMOylation in budding yeast.
    Austin Folger, Emily Gutierrez-Morton, Marie-Helene Kabbaj, Mark Tyler Campbell, Garret Morton, Timothy L Megraw, Yanchang Wang.
      Protein misfolding is linked to many neurodegenerative disorders, such as Huntington's disease. The increase of glutamine-encoding CAG repeats in the first exon of Huntingtin (HTT) causes Huntington's disease. Protein fragments of Htt exon 1 with polyQ expansion (mHtt) are prone to aggregation, resulting in oligomers, amyloid fibrils, or large inclusion bodies. Previous studies demonstrate mHtt SUMOylation, a process of covalent attachment of small ubiquitin-like modifiers (SUMOs) to target proteins. Protein polySUMOylation further triggers its ubiquitination and segregation by the polySUMO axis. Here, we examined how SUMOylation regulates aggregation and degradation of Htt103QP-GFP, a model mHtt, in budding yeast. We first confirmed Htt103QP-GFP SUMOylation in budding yeast. We also found that recruitment of the SUMO E2 conjugating enzyme to Htt103QP-GFP accelerates its aggregation, but recruitment of a SUMO protease to Htt103QP-GFP delays this process. Disruption of the polySUMO axis led to increased Htt103QP-GFP aggregation. Interestingly, the results from FRAP assay and treatment with a biomolecular condensate-disrupting chemical indicate that SUMOylation accelerates biomolecular condensate formation of Htt103QP-GFP. Importantly, impaired SUMOylation delays Htt103QP-GFP proteasomal degradation and accelerates formation of SDS-insoluble Htt103QP-GFP aggregates. Together, these results indicate that SUMOylation facilitates proteasomal degradation of misfolded proteins by retaining their solubility.
    DOI:  https://doi.org/10.1091/mbc.E24-12-0540
  15. Front Pharmacol. 2025 ;16 1519145
    Repurposing major metabolites of lamiaceae family as potential inhibitors of α-synuclein aggregation to alleviate neurodegenerative diseases: an in silico approach.
    Soham Bhattacharya, Neha Gupta, Adrish Dutta, Pijush Kanti Khanra, Ritesh Dutta, Jana Žiarovská, Nikolay T Tzvetkov, Lucie Severová, Lenka Kopecká, Luigi Milella, Eloy Fernández-Cusimamani.
      Neurodegenerative disorders (NDs) are typically characterized by progressive loss of neuronal function and the deposition of misfolded proteins in the brain and peripheral organs. They are molecularly classified based on the specific proteins involved, underscoring the critical role of protein-processing systems in their pathogenesis. Alpha-synuclein (α-syn) is a neural protein that is crucial in initiating and progressing various NDs by directly or indirectly regulating other ND-associated proteins. Therefore, reducing the α-syn aggregation can be an excellent option for combating ND initiation and progression. This study presents an in silico phytochemical-based approach for discovering novel neuroprotective agents from bioactive compounds of the Lamiaceae family, highlighting the potential of computational methods such as functional networking, pathway enrichment analysis, molecular docking, and simulation in therapeutic discovery. Functional network and enrichment pathway analysis established the direct or indirect involvement of α-syn in various NDs. Furthermore, molecular docking interaction and simulation studies were conducted to screen 85 major bioactive compounds of the Lamiaceae family against the α-syn aggregation. The results showed that five compounds (α-copaene, γ-eudesmol, carnosol, cedryl acetate, and spathulenol) had a high binding affinity towards α-syn with potential inhibitory activity towards its aggregation. MD simulations validated the stability of the molecular interactions determined by molecular docking. In addition, in silico pharmacokinetic analysis underscores their potential as promising drug candidates, demonstrating excellent blood-brain barrier (BBB) permeability, bioactivity, and reduced toxicity. In summary, this study identifies the most suitable compounds for targeting the α-syn aggregation and recommends these compounds as potential therapeutic agents against various NDs, pending further in vitro and in vivo validation.
    Keywords:  MD simulation; functional network analysis; molecular docking; neuroprotective agent; pathway enrichment analysis; phytochemical
    DOI:  https://doi.org/10.3389/fphar.2025.1519145
  16. ACS Chem Neurosci. 2025 May 01.
    Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.
    Zhengdong Xu, Wenjuan Yi, Lulu Guan, Jiaxing Tang, Dushuo Feng, Yu Zou.
      Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experiments identified that the ALS-linked familial variant, N352S (asparagine substituted by serine), and subsequent phosphorylation of S352 (S352p) are associated with the aggregation of TDP-43. However, the underlying molecular mechanisms are still not fully understood. By performing all-atom explicit-solvent replica exchange molecular dynamics (REMD) simulations with a total simulation time of 100.8 μs, we scrutinized the impact of the N352S mutation and its phosphorylation variant S352p on the conformational ensembles of the TDP-43342-366 dimer. Our simulation results show that both the N352S and S352p variants could promote the formation of unstructured conformation and impede the formation of β-structure and helix content, and the inhibitive effect of S352P is more obvious. Further analyses suggest that the H-bonding and hydrophobic interaction among TDP-43342-366 peptides, as well as the R361-E362 salt bridge, are attenuated by N352S and S352p variants. Additional MD simulations show that N352S and S352p variants reduce the structural stability of the hydrophobic region and lower the number of H-bonds and contacts of two hydrophobic clusters, thus possessing a destabilization effect on the TDP-43282-360 protofibrils. Our results unmask the molecular mechanism of the N352S mutation and its phosphorylation variant S352p toward the inhibition of TDP-43342-366 aggregation and prove the protofibril-destabilizing effects of these two variants, which may be helpful for designing drugs for the treatment of ALS.
    Keywords:  N352S mutation; TDP-43; aggregation; amyotrophic lateral sclerosis; molecular dynamics simulation; phosphorylation
    DOI:  https://doi.org/10.1021/acschemneuro.5c00045
  17. Sci Adv. 2025 May 02. 11(18): eadt5111
    Massive experimental quantification allows interpretable deep learning of protein aggregation.
    Mike Thompson, Mariano Martín, Trinidad Sanmartín Olmo, Chandana Rajesh, Peter K Koo, Benedetta Bolognesi, Ben Lehner.
      Protein aggregation is a pathological hallmark of more than 50 human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the aggregation of >100,000 protein sequences. This unprecedented dataset reveals the limited performance of existing computational methods and allows us to train CANYA, a convolution-attention hybrid neural network that accurately predicts aggregation from sequence. We adapt genomic neural network interpretability analyses to reveal CANYA's decision-making process and learned grammar. Our results illustrate the power of massive experimental analysis of random sequence-spaces and provide an interpretable and robust neural network model to predict aggregation.
    DOI:  https://doi.org/10.1126/sciadv.adt5111
  18. Neurochem Int. 2025 Apr 30. pii: S0197-0186(25)00055-5. [Epub ahead of print] 105982
    Truncation mutation of CHMP2B disrupts late endosome function but reduces TDP-43 aggregation through HSP70 upregulation.
    Yohei Iguchi, Yuhei Takahashi, Jiayi Li, Yoshinobu Amakusa, Yu Kawakami, Takashi Yoshimura, Ryo Chikuchi, Madoka Iida, Satoshi Yokoi, Masahisa Katsuno.
      TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantially to the neurodegeneration of ALS and FTLD. The endosome, a key component of membrane trafficking in eukaryotic cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B, are either causative or act as genetic modifiers in ALS and FTLD. However, the association between endosomal functions and TDP-43 aggregations remain poorly understood. The C-terminal truncation mutation CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts late endosome (LE)-lysosomes fusion. Nevertheless, FTD3 does not induce TDP-43 pathology. In this study, we showed that CHMP2B mutation-induced LE dysfunction promotes TDP-43 aggregate degradation through enhanced recruitment to juxtanuclear quality control compartments. Transcriptomic analysis revealed that CHMP2Bintron5 overexpression upregulates HSP70 expression. New insights into the connection between CMHP2B and HSP70 as well as the role of HSP70-mediated membrane trafficking in TDP-43 aggregation, offer a valuable understanding of the disease mechanism of ALS and FTLD.
    Keywords:  ALS; CHMP2B; FTD; TDP-43; endosome; juxtanuclear quality control compartment
    DOI:  https://doi.org/10.1016/j.neuint.2025.105982
  19. Nat Chem. 2025 Apr 30.
    Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds.
    Isaac J Angera, Xueyong Xu, Benjamin H Rajewski, Grace I Hallinan, Xiaoqi Zhang, Bernardino Ghetti, Ruben Vidal, Wen Jiang, Juan R Del Valle.
      Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or 'mini-tau', proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration.
    DOI:  https://doi.org/10.1038/s41557-025-01805-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒06 at 11:56.