bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–05–11
twenty-one papers selected by
Verena Kohler, Umeå University
  1. Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability.
  2. The thermodynamic hypothesis of protein aggregation.
  3. Small molecule-mediated therapeutic approaches to target Tau and Alzheimer's disease.
  4. Protein aggregation in health and disease: A looking glass of two faces.
  5. Exploring therapeutic strategies based on chaperon-mediated disaggregation.
  6. Parishin C modulates the amyloid transformation of alpha-synuclein protein by apparently interacting with the NAC domain.
  7. Novel strategies for targeting tau oligomers in neurodegenerative diseases.
  8. Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.
  9. Soluble N-Terminal Domain of the Prion Protein Interferes with Fibrillization of α-Synuclein to Form Off-Pathway Assemblies that Lack Cellular Seeding Activity.
  10. Intelligent Screening of Functional Small Molecules for Targeting Metal-Induced Protein Aggregation.
  11. α-Synuclein targeted therapy with multiple pathological improvement for Parkinson's disease by macrocyclic amphiphile nanomedicine.
  12. Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.
  13. Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.
  14. Autophagy in cancer and protein conformational disorders.
  15. Deciphering protein aggregation: Insights into morphology, contributing factors, and molecular pathologies.
  16. PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson's disease.
  17. AAV delivery of GBA1 suppresses α-synuclein accumulation in Parkinson's disease models and restores functions in Gaucher's disease models.
  18. Anti-parallel β-Sheet as a Key Motif of Amyloid-β Inhibitor Designed via Topological Peptide Reprogramming.
  19. Assessing amyloid fibrils and amorphous aggregates: A review.
  20. A Ginsenoside Composition Ameliorated Aβ and Tau Aggregation via Autophagy Lysosome Pathway.
  21. Hyperphosphorylated tau-based Alzheimer's Disease drug discovery: Identification of inhibitors of tau aggregation and cytotoxicity.
  1. Sci Rep. 2025 May 04. 15(1): 15597
    Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability.
    Elena A Ostrakhovitch, Eun-Suk Song, Johannah E Stegemann, Michael McLeod, Tritia R Yamasaki.
      Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.
    Keywords:  Hydrogen sulfide; Parkinson disease; Protein aggregation; α-Synuclein
    DOI:  https://doi.org/10.1038/s41598-025-99794-z
  2. Mol Aspects Med. 2025 May 03. pii: S0098-2997(25)00028-7. [Epub ahead of print]103 101364
    The thermodynamic hypothesis of protein aggregation.
    Michele Vendruscolo.
      Protein misfolding and aggregation drive some of the most prevalent and lethal disorders of our time, including Alzheimer's and Parkinson's diseases, now affecting tens of millions of people worldwide. The complexity of these diseases, which are often multifactorial and related to age and lifestyle, has made it challenging to identify the causes of the accumulation of aberrant protein deposits. An insight into the origins of these deposits comes from reports of a widespread presence of protein aggregates even under normal cellular conditions. This observation is best accounted for by the thermodynamic hypothesis of protein aggregation. According to this hypothesis, many proteins are expressed at levels close to their supersaturation limits, so that their native states are metastable against aggregation. Here we integrate the evidence behind this hypothesis and outline actionable therapeutic strategies that could halt protein aggregation at its source.
    DOI:  https://doi.org/10.1016/j.mam.2025.101364
  3. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00133-0. [Epub ahead of print]145 287-304
    Small molecule-mediated therapeutic approaches to target Tau and Alzheimer's disease.
    Subashchandrabose Chinnathambi.
      Neurodegeneration is marked by the altered proteostasis and protein degradation mechanism. This is caused due to the accumulation of aberrant proteins. Alzheimer's disease is one of the leading causes of neurodegeneration characterized by the aggregation of Tau and Amyloid-β proteins intracellularly and extracellularly, respectively. The intracellular aggregation of Tau triggers accumulation of oxidative stress, loss of ER and mitochondrial function, leading to the aggravation of aggregates formation. Thus, increasing the load of aberrant proteins on chaperones and degradative mechanism, such as autophagy and ubiquitin-proteasome system. Although several small molecules are known to target and prevent Tau aggregation, the detrimental effects in the cell due to aggregates accumulation shall not be overlooked. In such instance, small molecules that effectively target Tau aggregates and the cellular aberrations would be of great importance. Here we have discussed the efficacy of natural molecule, Limonoid, isolated from Azadirachta indica that prevents Tau aggregation and also activates the heat shock protein system. The activated heat shock protein system elevates the levels of Hsp70 that is known to interact with aberrantly folded Tau. Further, the role of Hsp70 in directing Tau clearance by macroautophagy or chaperone-mediated autophagy elucidates the effect of limonoids in overcoming AD pathology due to Tau aggregation.
    Keywords:  Aggregation; Alzheimer’s disease; Chaperones; Heat shock protein response; Limonoids; Proteostasis; Tau
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.11.010
  4. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00096-8. [Epub ahead of print]145 145-217
    Protein aggregation in health and disease: A looking glass of two faces.
    Guilherme C de Andrade, Michelle F Mota, Dinarte N Moreira-Ferreira, Jerson L Silva, Guilherme A P de Oliveira, Mayra A Marques.
      Protein molecules organize into an intricate alphabet of twenty amino acids and five architecture levels. The jargon "one structure, one functionality" has been challenged, considering the amount of intrinsically disordered proteins in the human genome and the requirements of hierarchical hetero- and homo-protein complexes in cell signaling. The assembly of large protein structures in health and disease is now viewed through the lens of phase separation and transition phenomena. What drives protein misfolding and aggregation? Or, more fundamentally, what hinders proteins from maintaining their native conformations, pushing them toward aggregation? Here, we explore the principles of protein folding, phase separation, and aggregation, which hinge on crucial events such as the reorganization of solvents, the chemical properties of amino acids, and their interactions with the environment. We focus on the dynamic shifts between functional and dysfunctional states of proteins and the conditions that promote protein misfolding, often leading to disease. By exploring these processes, we highlight potential therapeutic avenues to manage protein aggregation and reduce its harmful impacts on health.
    Keywords:  Aggregation; Amyloids; Cryogenic electron microscopy; Functional amyloids; Misfolding
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.09.010
  5. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00126-3. [Epub ahead of print]145 219-254
    Exploring therapeutic strategies based on chaperon-mediated disaggregation.
    Leandro Rocha Silva, Sheila Oliveira de Souza, Ana Catarina Rezende Leite, Edeildo Ferreira da Silva-Júnior.
      In the quest to develop effective therapeutic strategies for diseases associated with protein misfolding and aggregation, molecular chaperones have emerged as pivotal players. This chapter explores the role of chaperones, such as Hsp40, Hsp70, and Hsp90, in mediating the disaggregation of misfolded proteins and facilitating proper folding under stress conditions. Despite their lack of sequence specificity, these proteins adeptly recognize exposed hydrophobic regions in partially folded states, thereby preventing aggregation and promoting functional conformations. The intricate network of chaperone interactions is crucial for maintaining cellular homeostasis and mitigating the pathological consequences of protein misfolding, particularly in conditions like Alzheimer's disease and various cancers. Innovative therapeutic approaches, including the use of pharmacological and chemical chaperones, aim to restore functionality to mutated or misfolded proteins, exemplified by interventions targeting the ΔF508 mutation in CFTR. While promising, the modulation of chaperone activity must be carefully calibrated to avoid disrupting cellular functions. This chapter highlights the potential of chaperone-mediated disaggregation as a therapeutic strategy, addressing both the current advancements and the challenges that lie ahead in harnessing these proteins for clinical benefit.
    Keywords:  Chemical chaperones; Heat shock protein; Molecular chaperones; Protein disaggregation; Protein misfolding
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.11.003
  6. Biochim Biophys Acta Proteins Proteom. 2025 May 07. pii: S1570-9639(25)00014-7. [Epub ahead of print] 141076
    Parishin C modulates the amyloid transformation of alpha-synuclein protein by apparently interacting with the NAC domain.
    Almas Akhtar, Payal Singh, Nikita Admane, Abhinav Grover.
      Parkinson's disease (PD) is a neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons in the brain and the presence of Lewy bodies (LB) within the remaining affected neurons, comprised of α-synuclein protein aggregates. Herein, we report a novel amyloid inhibitory potential of Parishin C on the amyloid transformation of the α-synuclein protein. Our studies involving computational screening and REMD simulation analysis revealed a strong interaction between Parishin C and the non-amyloid component (NAC domain), a known aggregation-prone region of the α-synuclein protein. Thioflavin T fluorescence assay demonstrated the inhibitory effect of Parishin C on amyloid transformation kinetics of α-synuclein, where even at the lowest concentration of Parishin C there was a 72 % reduction in the ThT maxima. ANS binding assay further revealed its ability to alter the surface hydrophobicity of the protein. An extensive evaluation using biophysical techniques indicated that Parishin C effectively prevented the formation of mature fibrillar species and promoted the formation of lower order aggregates with reduced cross-β-sheet signatures compared to the native α-synuclein aggregates. Collectively, our research highlights Parishin C's potential as a structural blueprint for developing new therapeutic compounds aimed at preventing the amyloidogenic transition in Parkinson's disease and related disorders.
    Keywords:  Amyloid transformation; Biophysical characterization; In-silico screening; Parishin C; REMD simulation; α-synuclein
    DOI:  https://doi.org/10.1016/j.bbapap.2025.141076
  7. J Neurol. 2025 May 08. 272(6): 383
    Novel strategies for targeting tau oligomers in neurodegenerative diseases.
    Jing Lin, Hong Li, Lingxia Jiang, Jian Li.
      Tau protein is a soluble microtubule-associated protein enriched in neurons, is mainly distributed in the central nervous system, and is responsible for stabilizing neurons. Tau maintains nerve cell morphology and internal transport by binding to normal microtubules. In neurodegenerative diseases, such as Alzheimer's disease (AD), tau proteins undergo aberrant phosphorylation, resulting in their removal from microtubules and the formation of neurofibrillary tangles (NFTs), which are key pathological features. In contrast to the late formation of non-soluble NFTs, early, smaller, soluble tau oligomers (tauO) with disseminated toxicity are considered necessary in neurodegenerative disorders, such as the primary form of tau toxicity in the AD process. Although an increasing number of studies are focusing on tauO, there are still problems to be solved, mainly concerning the molecular and inhibitory mechanisms of tauO toxicity. In this paper, we summarize the new strategies for the molecular mechanisms of tauO toxicity, detection methods, and interventions in the last five years. An outlook on these new strategies and the challenges that may be foreseen is presented to provide new directions for future applications in the clinical treatment of neurodegenerative diseases.
    Keywords:  Alzheimer's disease; Neurodegenerative diseases; Tau; Tau oligomers
    DOI:  https://doi.org/10.1007/s00415-025-13117-w
  8. Basic Res Cardiol. 2025 May 07.
    Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.
    Nirjal Mainali, Meenakshisundaram Balasubramaniam, Sonu Pahal, W Sue T Griffin, Robert J Shmookler Reis, Srinivas Ayyadevara.
      Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated. We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways. In this study, we further investigate the molecular mechanisms altered by induced MI in mice, which were also implicated by proteomics of postmortem human hippocampal aggregates from Alzheimer's disease (AD) and cardiovascular disease (CVD) patients, vs. age-matched controls (AMC). We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes). We used leave-one-out analysis (LOOA) to determine the contribution of each protein to overall aggregate cohesion, and gene ontology meta-analyses of constituent proteins to define critical organelles, processes, and pathways that distinguish AD and/or CVD from AMC aggregates. We identified influential proteins in both AD and CVD aggregates, many of which are associated with pathways or processes previously implicated in neurodegeneration such as mitochondrial, oxidative, and endoplasmic-reticulum stress; protein aggregation and proteostasis; the ubiquitin proteasome system and autophagy; axonal transport; and synapses.
    Keywords:  Alzheimer’s disease; Cardiovascular disease; Crosslinking studies; Leave-one-out analysis; Protein aggregates
    DOI:  https://doi.org/10.1007/s00395-025-01109-w
  9. ACS Chem Neurosci. 2025 May 07.
    Soluble N-Terminal Domain of the Prion Protein Interferes with Fibrillization of α-Synuclein to Form Off-Pathway Assemblies that Lack Cellular Seeding Activity.
    Prerna Grover, Robert Dec, Fatemeh Mamashli, Roland Winter, Konstanze F Winklhofer, Jörg Tatzelt.
      Disease progression in synucleinopathies is associated with the formation of seeding-competent α-synuclein (αSyn) aggregates. After spreading and cellular uptake, the αSyn seeds propagate in a prion-like mechanism by inducing the conversion of natively folded αSyn into pathogenic aggregates. Here we show that the soluble intrinsically disordered N-terminal domain of the cellular prion protein (N1-PrP) modulates fibrillization of αSyn to form off-pathway aggregates that lack seeding activity in cells. N1-PrP does not interact with soluble αSyn. However, during the aggregation of αSyn in vitro, N1-PrP is recruited and incorporated. As a result, amorphous coaggregates are formed instead of seeding-competent αSyn fibrils. Similarly, in the cytosol of neuronal cells N-PrP specifically interacts with αSyn during the prion-like propagation of pathogenic αSyn seeds. These findings identify a unique neuroprotective activity of the soluble N-terminal domain of the prion protein by promoting off-pathway reactions in amyloid seed formation.
    Keywords:  neurodegeneration; prion; proteinopathies; seeding; spreading; α-synuclein
    DOI:  https://doi.org/10.1021/acschemneuro.5c00085
  10. Anal Chem. 2025 May 06.
    Intelligent Screening of Functional Small Molecules for Targeting Metal-Induced Protein Aggregation.
    Cong Xiao, Jiaqi Shi, Jingyu Yan, Ruiqi Xiao, Yizhu Wang, Huiqin Yao, Lingchen Meng, Hongyun Liu, Lanqun Mao.
      Screening small-molecule drugs to suppress protein aggregation and the production of reactive oxygen species (ROS) is one of the primary directions for drug development in neurodegenerative diseases (NDs). However, current methods often have difficulty in striking a balance between accuracy and simplicity. In this work, we constructed active peptide interfaces to intelligently screen potential drugs for metal-induced protein aggregation with a logic network. Taking β-amyloid peptide (Aβ), which is closely related to Alzheimer's disease (AD), as an example, we covalently connected Aβ onto the gold electrode surface and characterized the aggregation state of Aβ induced by copper ions (Cu(II)) through electrochemical impedance spectroscopy (EIS). The formed Aβ-Cu(II) complex interfaces were also used to study the catalytic production of ROS and the ameliorative effect of potential drugs on oxidative stress by the ultraviolet (UV) spectrum of ascorbic acid (AA). By constructing a comparator logic network using EIS and UV signals, the potential small molecules targeting Aβ-Cu(II) aggregations could be classified into 4 different types of effects. Transmission electron microscopy (TEM), cytotoxicity, and ROS assays were used to verify the reliability of the classification. The corresponding results of using α-synuclein (α-Syn) instead of Aβ indicated that this intelligent screening platform might provide a general route for potential NDs' drug screening.
    DOI:  https://doi.org/10.1021/acs.analchem.5c00439
  11. Biomaterials. 2025 Apr 25. pii: S0142-9612(25)00297-2. [Epub ahead of print]322 123378
    α-Synuclein targeted therapy with multiple pathological improvement for Parkinson's disease by macrocyclic amphiphile nanomedicine.
    Jian-Mei Gao, Wen-Bo Li, Yang Yi, Jia-Jia Wei, Miao-Xian Gong, Bin-Bin Pan, Xun-Cheng Su, Yu-Chen Pan, Dong-Sheng Guo, Qi-Hai Gong.
      The toxic species formed by the pathological aggregation of α-synuclein (α-Syn) is one of the core pathogenic mechanisms in Parkinson's disease, leading to mitochondrial dysfunction, oxidative stress and ultimately degeneration and loss of dopaminergic neurons. Developing effective inhibitors targeting α-Syn fibrillization critically requires the simultaneous achievement of (1) strong and selective binding of α-Syn for efficient disintegration of fibrils, as well as (2) robust transmembrane capability for efficient cellular uptake. Herein, the co-assembly of guanidinium-modified calixarene (GCA) and cyclodextrin (CD), termed GCA-CD, is screened fully accommodating these conditions. GCA-CD binds tightly and selectively towards α-Syn, thereby effectively inhibiting α-Syn aggregation and disintegrating its fibrils, meanwhile the guanidinium of GCA can additionally improve the transmembrane capability of the co-assembly. In vivo investigations demonstrate that the GCA-CD nanomedicine significantly rescues motor deficits and nigrostriatal degeneration of PD-like rats by decreasing the content of α-Syn as well as restoring mitochondrial dysfunction and suppressing oxidative stress. Astonishingly, transcriptome analysis further reveals the role of GCA-CD in dampening cuproptosis through inhibiting FDX1/LIAS signaling pathway, highlighting the multifaceted therapeutic effects of the co-assembly in PD. The findings in this study underscore the comprehensive exposition on the actual function mechanisms of the therapeutic agents, thereby providing valuable insights for informing material design.
    Keywords:  Cuproptosis; Fibril disintegration; Molecular recognition; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123378
  12. Mol Neurodegener. 2025 May 08. 20(1): 53
    Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.
    Elise A Kellett, Adekunle T Bademosi, Adam K Walker.
      Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.
    Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; Kinase; Neurodegeneration; Phosphatase; Phosphorylation; Post-translational modifications; TDP-43
    DOI:  https://doi.org/10.1186/s13024-025-00839-8
  13. Chem Rev. 2025 May 06.
    Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.
    Timothy S Chisholm, Christopher A Hunter.
      Amyloid fibrils are characteristic features of many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. The use of small molecule ligands that bind to amyloid fibrils underpins both fundamental research aiming to better understand the pathology of neurodegenerative disease, and clinical research aiming to develop diagnostic tools for these diseases. To date, a large number of amyloid-binding ligands have been reported in the literature, predominantly targeting protein fibrils composed of amyloid-β (Aβ), tau, and α-synuclein (αSyn) fibrils. Fibrils formed by a particular protein can adopt a range of possible morphologies, but protein fibrils formed in vivo possess disease-specific morphologies, highlighting the need for morphology-specific amyloid-binding ligands. This review details the morphologies of Aβ, tau, and αSyn fibril polymorphs that have been reported as a result of structural work and describes a database of amyloid-binding ligands containing 4,288 binding measurements for 2,404 unique compounds targeting Aβ, tau, or αSyn fibrils.
    DOI:  https://doi.org/10.1021/acs.chemrev.4c00838
  14. FEBS Lett. 2025 May 08.
    Autophagy in cancer and protein conformational disorders.
    Sergio Attanasio.
      Autophagy is a catabolic process by which cells maintain cellular homeostasis through the degradation of dysfunctional cytoplasmic components, such as toxic misfolded proteins and damaged organelles, within the lysosome. It is a multistep process that is tightly regulated by nutrient, energy, and stress-sensing mechanisms. Autophagy plays a pivotal role in various biological processes, including protein and organelle quality control, defense against pathogen infections, cell metabolism, and immune surveillance. As a result, autophagy dysfunction is linked to a variety of pathological conditions. The role of autophagy in cancer is complex and dynamic. Depending on the context, autophagy can have both tumor-suppressive and pro-tumorigenic effects. In contrast, its role is more clearly defined in protein conformational disorders, where autophagy serves as a mechanism to reduce toxic protein aggregation, thereby improving cellular homeostasis. Because autophagy-based therapies hold promising potential for the treatment of cancer and protein conformational disorders, this review will highlight the latest findings and advancements in these areas.
    Keywords:  RAS‐ and RAF‐induced cancer; alpha‐1 antitrypsin deficiency; autophagy; autophagy inhibitors; clinical trials; neurodegenerative disorders; pancreatic ductal adenocarcinoma; protein misfolding; proteinopathies
    DOI:  https://doi.org/10.1002/1873-3468.70061
  15. Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00132-9. [Epub ahead of print]145 23-71
    Deciphering protein aggregation: Insights into morphology, contributing factors, and molecular pathologies.
    Sree Hima, N Aiswarya, Chandran Remya, D M Vasudevan, K V Dileep, Dileep Francis.
      Protein aggregation research stands at the cutting edge of biomedical science, offering crucial insights into the molecular underpinnings of neurodegenerative and amyloid-associated diseases. Significant advancements in deciphering the structural, biophysical, and molecular intricacies of protein misfolding are driving the development of innovative therapies. Emerging approaches, from small molecule inhibitors to sophisticated polymer-based therapeutics, hold great promise for alleviating the toxic impacts of aggregation with the potential to prevent, delay, or even reverse disease progression. Despite these advances, the field contends with substantial challenges. The polymorphic and complex nature of protein aggregates poses major obstacles to both research and therapeutic design. Yet, interdisciplinary methodologies-integrating advanced spectroscopic, imaging, and computational tools-are creating new pathways to address these complexities, effectively bridging molecular breakthroughs and practical therapeutic applications. The rapid shift of foundational discoveries to clinical trials marks a pivotal step forward, instilling new hope for patients with protein aggregation disorders. Each breakthrough propels us closer to life-changing therapies that may reshape the outlook for these patients. The promise of precise and effective treatments is driving a transformative shift in medical science, establishing protein aggregation research as a crucial pillar in combating these challenging diseases and offering a beacon of hope for the future of neurodegenerative care.
    Keywords:  Aggregation; Aggregation mechanisms; Amyloid fibrils; Oligomers; Steric zipper
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.11.009
  16. Neuropeptides. 2025 May 06. pii: S0143-4179(25)00022-8. [Epub ahead of print]111 102522
    PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson's disease.
    Maryam Motamedi, Dina Morshedi, Najaf Allahyari Fard.
      The accumulation of alpha-synuclein (⍺-Syn) fibrils plays a central role in the progression of Parkinson's disease (PD) and related neurodegenerative disorders. In this context, the development of peptide inhibitors designed to inhibit ⍺-Syn through computational methods has emerged as a promising area of research. This study focused on developing a peptide inhibitor, PQK7, designed based on the key residues of NAC region of ⍺-Syn fibrils involved in its aggregation. Using molecular docking and dynamics simulations, PQK7 was shown to bind key residues in the NAC region of ⍺-Syn (Val-74, Ala-76, Val-77, Thr-81, Ser-87, Ile-88, and Ala-89), effectively disrupting the formation of fibrils. MD simulations indicated that the PQK7-⍺-Syn complex reaches a stable conformation, which showed increased fluctuations and reduced β-sheet content, suggests that PQK7 interferes with ⍺-Syn fibrillation at the molecular level. In vitro assays like ThT fluorescence assay, AFM imaging, CD specotroscopy, and SDS-PAGE analysis confirmed that PQK7 significantly reduces ⍺-Syn fibril formation, particularly at substoichiometric concentrations, while keeping ⍺-Syn monomers in a soluble state. Additionally, PQK7-⍺-Syn treatment in SH-SY5Y cells reduced the toxicity of ⍺-Syn aggregates, restoring normal cell cycle progression and reducing apoptosis and oxidative stress. Our findings suggest that PQK7 holds potential as a therapeutic agent for PD, acting as an anti-oligomeric inhibitor that targets early ⍺-Syn aggregates without affecting the protein's normal function.
    Keywords:  Alpha-synuclein; Fibrillation; Neurodegenerative diseases; Parkinson's disease; Peptide inhibitors
    DOI:  https://doi.org/10.1016/j.npep.2025.102522
  17. PLoS One. 2025 ;20(5): e0321145
    AAV delivery of GBA1 suppresses α-synuclein accumulation in Parkinson's disease models and restores functions in Gaucher's disease models.
    Takuro Okai, Sho Sato, Mugdha Deshpande, Shin-Ichi Matsumoto, Miyu Nakayama, Syunsuke Yamamoto, Bettina Strack-Logue, Takeshi Hioki, Maiko Tanaka, Gabriele Proetzel.
      Biallelic mutations in the glucosylceramidase beta 1 (GBA1) gene are the underlying genetic cause of Gaucher's disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently, GBA1 mutations have been identified as the most prevalent genetic risk factor for Parkinson's disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the α-synuclein pathology is more prominent, and recent data suggest a link between α-synucleinopathies and GBA1 mutations. Here, we explored the effect of GBA1 gene supplementation on the GD phenotypes and α-synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the same in vitro and in vivo. GBA1 overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate that GBA1 overexpression can dissolve phospho-α-synuclein aggregation induced by the addition of α-synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of β-Glucocerebrosidase (GCase) on α-synuclein accumulation. In vivo, we show that GCase inhibition can induce insoluble high-molecular-weight α-synuclein aggregation and that delivery of GBA1 achieves robust reduction of the α-synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes α-synuclein aggregates which are the hallmark for PD and α-synucleinopathies. AAV delivery of GBA1 is a powerful approach to restore glucocerebrosidase function and to resolve misfolded α-synuclein protein, with applications for GD and PD.
    DOI:  https://doi.org/10.1371/journal.pone.0321145
  18. Angew Chem Int Ed Engl. 2025 May 09. e202504640
    Anti-parallel β-Sheet as a Key Motif of Amyloid-β Inhibitor Designed via Topological Peptide Reprogramming.
    Dongjoon Im, Ye Eun Lee, Gyusub Yoon, William A Goddard, Tae Su Choi, Hugh I Kim.
      Aggregation of amyloidogenic intrinsically disordered proteins (IDPs) such as amyloid-β (Aβ) is associated with the pathogenesis of Alzheimer's disease (AD). Peptide inhibitors targeting Aβ peptide represents a promising strategy to disrupt its pathogenic self-assembly. Conventional inhibitor design primarily mimics repetitive sequences found in fibrillar Aβ assemblies. However, since the structural dynamics of Aβ involves in the early-stage oligomerization, its conformational flexibility should be considered in sequence-based design principle. Herein, we introduce topological reprogramming of peptide inhibitors to induce the structural transformation in pathogenic Aβ 1-42 (Aβ42). The eleven-residue peptide scaffold Pa11 (14HQKLVNFAEDV24) identified through the initial screening was dimerized via a disulfide bond. The dimerization stabilizes local Aβ42 structures by promoting anti-parallel β-sheet conformations in the scaffolds, thereby significantly suppressing Aβ42 aggregation. Our approach underscores that conformational features of IDPs can be modulated through the modification in peptide connectivity, suggesting a novel strategy for Aβ-targeted peptide building block.
    Keywords:  Alzheimer's disease; Amyloid aggregation; Oligomers; intrinsically disordered proteins; peptides and proteins
    DOI:  https://doi.org/10.1002/anie.202504640
  19. Int J Biol Macromol. 2025 May 03. pii: S0141-8130(25)04277-1. [Epub ahead of print]311(Pt 3): 143725
    Assessing amyloid fibrils and amorphous aggregates: A review.
    Shaik Basha, Darshan Chikkanayakanahalli Mukunda, Aparna Ramakrishna Pai, Krishna Kishore Mahato.
      Protein misfolding and aggregation play a central role in the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's. These aggregates manifest either as structured amyloid fibrils enriched in β-sheet conformations or as irregular amorphous aggregates with diverse morphologies. Understanding their formation, structure, and behavior is critical for deciphering disease mechanisms and developing targeted diagnostics and therapeutics. This review presents an integrated overview of both conventional and advanced techniques used to detect, distinguish, and structurally characterize these protein aggregates. It covers a range of spectroscopic and spectrometric tools, such as fluorescence, Raman, and mass spectrometry that facilitate aggregate identification. Microscopy methods, including atomic force and electron microscopy, are highlighted for morphological analysis. The review also discusses in situ detection strategies using fluorescent dyes, conformation-specific antibodies, enzymatic reporters, and real-time imaging. Separation methods like centrifugation, electrophoresis, and chromatography are outlined alongside structural analysis tools such as X-ray diffraction. Furthermore, the growing utility of computational approaches and artificial intelligence in predicting aggregation propensities and integrating biological data is emphasized. By critically evaluating each method's capabilities and limitations, this review provides a practical and forward-looking resource for researchers studying the complex landscape of protein aggregation.
    Keywords:  Amorphous aggregates; Amyloid fibrils; Analytical techniques; Neurodegenerative disorders; Protein aggregation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143725
  20. Mol Neurobiol. 2025 May 06.
    A Ginsenoside Composition Ameliorated Aβ and Tau Aggregation via Autophagy Lysosome Pathway.
    Chengmu Zhao, Juan Yue, Yu Xie, Bo Liu, Shuaishuai Xu, Dejuan Zhi, Dongsheng Wang.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the abnormal deposition of amyloid-beta (Aβ) peptides and neurofibrillary tangles (NFTs). Ginsenosides, the primary active constituents in ginseng, exhibit potential in combating AD. In our previous work, the ginsenoside SumI was demonstrated to have superior anti-AD activity compared to other ginsenosides when used alone. This study revealed that SumI effectively decreased the lysosomal pH, promoted autophagosome formation, increased autophagic flux, and facilitated the transport of misfolded proteins to lysosomes for degradation in Caenorhabditis elegans. SumI activated the HLH-30 transcription factor by triggering a lipid-catabolic response akin to starvation. bec-1 RNAi significantly abrogated the anti-AD effect of SumI. Our findings indicate that SumI mitigated protein aggregation by activating the autophagy-lysosome pathway in C. elegans and provide scientific evidence that ginsenoside composition could be a potential therapeutic agent for treating or preventing AD.
    Keywords:  Alzheimer’s disease; Autophagosomes; Autophagy; Ginsenoside composition; Starvation-like effect
    DOI:  https://doi.org/10.1007/s12035-025-05017-x
  21. SLAS Discov. 2025 May 03. pii: S2472-5552(25)00028-0. [Epub ahead of print]33 100235
    Hyperphosphorylated tau-based Alzheimer's Disease drug discovery: Identification of inhibitors of tau aggregation and cytotoxicity.
    Hsiao-Tien Hagar, Virneliz Fernandez-Vega, Kuang-Wei Wang, Luis M Ortiz Jordan, Justin Shumate, Louis Scampavia, April Sweet Tapayan, Hien M Nguyen, Timothy P Spicer, Min-Hao Kuo.
      Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 30 million people worldwide. Underlying the progressive decline of cognitive functions are the neurofibrillary tangles (NFTs) in neurons of the brain. The spatiotemporal distribution of NFTs predicts the progression of cognitive symptoms. In contrast, the senile plaques of amyloid-β aggregates, another major biomarker for AD, do not correlate with the clinical symptom development, consistent with the negligible benefits to cognitive functions in patients receiving anti-Aβ immunotherapies. A new drug discovery avenue targeting tau pathologies is therefore urgently needed. Using a recombinant hyperphosphorylated tau (p-tau) that presents characters key to the disease, e.g., formation of neurotoxic aggregates, we conducted a fluorescence p-tau aggregation assay and completed a 100K-compound high-throughput screen (HTS) and identified inhibitors of p-tau aggregation and cytotoxicity. This dual functional screen resulted in several potent compounds that effectively curbed both p-tau aggregation and cytotoxicity. Results presented in this work are the first HTS for small-molecule compounds that target the cellular toxicity of hyperphosphorylated tau. Top hits found in this screen and their analogues to be developed in the near future may lead to breakthroughs in the therapeutic development for Alzheimer's disease and other neurodegenerative tauopathies.
    Keywords:  Aggregation; Alzheimer’s disease; Amyloid; CNS; Fluorescence; Hts; Hyperphosphorylated tau; Inhibitor; Pharmacological inhibitors
    DOI:  https://doi.org/10.1016/j.slasd.2025.100235
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