bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–03–09
ten papers selected by
Verena Kohler, Umeå University
  1. Modulation of α-Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid.
  2. Inspecting the Triazole Scaffold as Powerful Antifibril Agents against 2N4R Tau and α-Synuclein Aggregates.
  3. The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.
  4. Autoantibodies against α-synuclein inhibit its aggregation and cytotoxicity.
  5. Rationally designed peptides inhibit the formation of α-synuclein fibrils and oligomers.
  6. Unnatural foldamers as inhibitors of Aβ aggregation via stabilizing the Aβ helix.
  7. Therapeutic Treatment With OLX-07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy.
  8. Nalidixic acid inhibits the aggregation of HSA: Utilizing the molecular simulations to uncover the detailed insights.
  9. Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.
  10. Potential role of ochratoxin A in Parkinson's disease: a systematic review of current evidence.
  1. ACS Chem Neurosci. 2025 Feb 28.
    Modulation of α-Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid.
    Kristos Baffour, Neelima Koti, Tony Nyabayo, Sathvika Balerao, Carissa Sutton, David Johnson, Rishi Patel, Santimukul Santra, Tuhina Banerjee.
      The protein misfolding and aggregation of α-synuclein (α-Syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Emerging evidence suggests that 4-phenylbutyrate (PBA) may play a role as a potential chemical chaperone for targeting α-Syn aggregation, but its molecular mechanism remains largely unknown. Using in vitro assays, we demonstrate that PBA treatment alters the pattern of α-Syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K (PK) assays, surface plasmon resonance (SPR), Nile red assays, and cytotoxicity assays indicate that PBA interacts with the extensive hydrophobic contacts of α-Syn oligomers and significantly reduces α-Syn-amyloid-induced toxicity. Furthermore, using thioflavin T-based assays, we elucidated the kinetics of PBA-mediated modulation of α-Syn aggregation, highlighting its role in accelerating the formation of α-Syn amyloid fibrils. Molecular dynamics (MD) simulations suggest PBA's role in the destabilization of the C-terminus in α-Syn oligomers through multiple residue interactions. Collectively, our findings provide compelling evidence for the neuroprotective potential of PBA in targeting protein misfolding and aggregation in PD and suggest an avenue for disease-modifying interventions in neurodegenerative disorders.
    Keywords:  4-phenylbutyric acid; amyloid protein; molecular dynamics simulations; oligomers; α-synuclein fibrillation
    DOI:  https://doi.org/10.1021/acschemneuro.4c00709
  2. ACS Omega. 2025 Feb 25. 10(7): 6721-6734
    Inspecting the Triazole Scaffold as Powerful Antifibril Agents against 2N4R Tau and α-Synuclein Aggregates.
    Ahmed A Elbatrawy, Taiwo A Ademoye, Heba Alnakhala, Arati Tripathi, Xiongwei Zhu, Germán Plascencia-Villa, George Perry, Ulf Dettmer, Jessica S Fortin.
      Alzheimer's (AD) and Parkinson's (PD) disease are neurodegenerative disorders that are considered to be a significant global health challenge due to their increasing prevalence and profound impact on both individuals and society. These disorders are characterized by the progressive loss of neuronal function, leading to cognitive and motor impairments. A key pathological feature of AD and PD is the abnormal accumulation of misfolded proteins within the brain. In AD, amyloid-beta aggregates into plaques, while tau proteins form neurofibrillary tangles (NFTs). Parkinson's disease, on the other hand, is marked by the accumulation of α-synuclein (α-syn) in the form of Lewy bodies (LBs). These protein aggregates are involved in neuronal dysfunction and neurodegeneration, contributing to disease progression. Research efforts are increasingly focused on identifying small molecules that can simultaneously target multiple pathological processes, offering the potential to not only alleviate symptoms but also modify the progression of neurodegeneration. Herein, a novel group of triazole-based compounds was designed and synthesized to curtail the aggregation of α-syn and tau proteins, which are closely linked to the physiopathology of PD and AD, respectively. A thioflavin T (ThT) fluorescence assay was used to measure fibril formation and assess the antiaggregation effects of various compounds. To further validate these findings, transmission electron microscopy (TEM) was employed as a direct method to visualize the impact of these compounds on fibril morphology. Inhibition of oligomer formation was evaluated using photoinduced cross-linking of unmodified proteins (PICUP), enabling the detection of early protein aggregation events. During fibril formation assays, three compounds (3e, 4b, 4d) demonstrated superior inhibitory activity as assessed by ThT fluorescence and TEM imaging. Subsequent evaluations, which included tests for antioligomer, anti-inclusion, and disaggregation effects identified compound 4d as the most promising candidate overall.
    DOI:  https://doi.org/10.1021/acsomega.4c08385
  3. Brain Commun. 2025 ;7(2): fcaf087
    The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration.
    Muhammet M Öztürk, Jakob Emgård, Juan García-Revilla, Rosalía Fernández-Calle, Yiyi Yang, Tomas Deierborg, Tomas T Roos.
      Numerous neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain's innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.
    Keywords:  Microglia; alpha-synuclein; amyloid-beta; prion-like; tau
    DOI:  https://doi.org/10.1093/braincomms/fcaf087
  4. J Autoimmun. 2025 Mar 03. pii: S0896-8411(25)00035-6. [Epub ahead of print]152 103390
    Autoantibodies against α-synuclein inhibit its aggregation and cytotoxicity.
    Carmen Noelker, Florian Seitz, Annekathrin Sturn, Frauke Neff, Luminita-Cornelia Andrei-Selmer, Lorenz Rau, Armin Geyer, J Alexander Ross, Michael Bacher, Richard Dodel.
      Aggregates of α-synuclein (α-Syn) are the major component of the Lewy bodies associated with Parkinson's disease. Recently, naturally occurring autoantibodies against α-synuclein (α-Syn-nAbs) were detected. Herein we have isolated and further characterized such α-Syn-nAbs. Using an affinity column coated with α-Syn, we have isolated α-Syn-nAbs from a commercially available intravenous Immunoglobulin (IVIg) preparation. A methodological approach based on ELISA, Western blotting and immunoprecipitation as well as surface plasmon resonance, was used to determine binding capacity to α-Syn. The epitope was determined via peptide array membrane and the functionality was tested in vitro using a toxicity and a fibrillation assay. The autoantibodies display strong binding capacity to α-Syn as demonstrated by ELISA, immunoprecipitation and Western blotting analysis. The binding affinities of the purified autoantibodies were analyzed in detail by surface plasmon resonance (Biacore). The epitope on α-Syn that is recognized by the α-Syn nAbs was fully determined. A sequence within the non-amyloid component (NAC)-Region of α-Syn is crucial for the binding of α-Syn-nAbs to α-Syn. Furthermore, the α-Syn-nAbs had an inhibitory effect on α-Syn fibril formation and were also able to specifically reverse the toxicity of α-Syn oligomers species in human neuroblastoma (SH-SY5Y) cells. Our results emphasize the possible importance of naturally occurring autoantibodies for the pathogenesis of Parkinson's disease. Since autoantibodies against α-Syn are detectable in human serum and cerebrospinal fluid and interfere with pathological events associated with α-Syn, they may provide a candidate for the treatment of Parkinson's disease.
    Keywords:  Autoantibodies; Intravenous immunoglobulins; Parkinson's disease; Synuclein
    DOI:  https://doi.org/10.1016/j.jaut.2025.103390
  5. Eur J Med Chem. 2025 Feb 26. pii: S0223-5234(25)00217-X. [Epub ahead of print]289 117452
    Rationally designed peptides inhibit the formation of α-synuclein fibrils and oligomers.
    Tariq T Ali, Madiha Merghani, Mohammed Al-Azzani, Luisa Maria Gatzemeier, Michael Hoppert, Dora Kaloyanova, Tiago F Outeiro, Piotr Neumann, Blagovesta Popova, Gerhard H Braus.
      Parkinson's Disease (PD) is characterized by the pathological aggregation of α-synuclein (αSyn) into oligomers and amyloid fibrils, making αSyn aggregation a key target for drug development. Peptides have gained recent attention as potential agents to inhibit aggregation. Two previously identified peptide inhibitors, discovered through large-scale yeast screening, were used as templates for in silico mutagenesis aimed at designing novel peptides with improved efficacy in inhibiting αSyn aggregation and cytotoxicity. The newly designed peptides underwent in silico docking analysis, and the most promising candidates were tested in vitro and in cellular models. Peptides T02 and T05 emerged as the most effective inhibitors, with T02 binding αSyn monomers and T05 targeting lower-order oligomers. Both peptides reduce αSyn fibril and oligomer formation in vitro and significantly suppress αSyn aggregation and cytotoxicity in yeast and human H4 cells. These novel peptides represent antagonists of αSyn aggregation with promising potential for therapeutic intervention for PD.
    Keywords:  Alpha-synuclein; Alpha-synuclein oligomerization; Parkinson disease; Peptide drug discovery; Protein aggregation; Rational peptide design
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117452
  6. Chem Commun (Camb). 2025 Mar 04.
    Unnatural foldamers as inhibitors of Aβ aggregation via stabilizing the Aβ helix.
    Heng Liu, Xue Zhao, Jianyu Chen, Yu Yu Win, Jianfeng Cai.
      Protein aggregation is a critical factor in the development and progression of several human diseases, including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and type 2 diabetes. Among these conditions, AD is recognized as the most prevalent progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) peptides. Neuronal toxicity is likely driven by soluble oligomeric intermediates of the Aβ peptide, which are thought to play a central role in the cascade leading to neuronal dysfunction and cognitive decline. In response, numerous therapeutic strategies have been developed to inhibit Aβ oligomerization, as this is believed to delay the formation of Aβ protofibrils. Traditional research has focused on discovering small molecules or peptides that antagonize Aβ oligomerization. However, recent studies have explored an alternative approach-developing ligands that stabilize the Aβ peptide in its α-helical conformation. This stabilization is thought to alter the peptide's natural aggregation kinetics, shifting it away from toxic oligomer formation and toward less harmful states. Crucially, by maintaining Aβ in this α-helical form, these ligands have been shown to rescue the peptide's associated cytotoxicity, offering a promising mechanism to mitigate the detrimental effects of Aβ in AD. While challenges remain, including treatment costs and side effects like ARIA (amyloid-related imaging abnormalities), anti-Aβ drug development represents a major advancement in Alzheimer's research and therapeutic options. This brief review aims to highlight the development and potential of these α-helix-stabilizing ligands as antagonists of Aβ aggregation, focusing on their interactions with Aβ and how these compounds induce and maintain secondary structural changes in the Aβ peptide. Notably, this innovative strategy holds promise beyond Aβ-related pathology, as the fundamental principles could be applied to other amyloidogenic proteins implicated in various amyloid-related diseases, potentially broadening the scope of therapeutic intervention for multiple neurodegenerative conditions.
    DOI:  https://doi.org/10.1039/d4cc05280c
  7. J Neurochem. 2025 Mar;169(3): e70025
    Therapeutic Treatment With OLX-07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy.
    E J Davidowitz, P Lopez, D Patel, H Jimenez, A Wolin, J Eun, L Adrien, J Koppel, D Morgan, P Davies, J G Moe.
      Targeting tau protein is a strategy for the development of disease-modifying therapeutics for Alzheimer's disease (AD) and numerous rare tauopathies. A small molecule approach targeting tau aggregation was used to select and optimize compounds inhibiting tau self-association in vitro that have translated in vivo in preventive studies in htau and P301L tau JNPL3 mouse models of tauopathy. In this therapeutic treatment study, aged JNPL3 mice with pre-existing tau aggregates were used to evaluate the therapeutic effect of OLX-07010. The study had a Baseline group of mice aged 7 months, a vehicle, and two dose groups treated until 12 months by administration in feed. The primary endpoint of the study was the reduction of insoluble tau aggregates with statistical significance. The secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of soluble tau, and improvement of motor behavior. ELISAs and immunoblots were used to determine the levels of tau and its aggregated forms including self-associated tau and Sarkosyl insoluble tau. Effect on motor behavior, as measured by Rotarod assay, was also assessed between the treatment groups. At the end of treatment, reduced levels of self-associated tau, Sarkosyl insoluble tau aggregates, and overall levels of tau in the heat-stable fraction with statistical significance in the cortex were observed. Treatment prevented the accumulation of tau aggregates above baseline, and in parallel, treatment groups had improved motor behavior in a Rotarod assay compared to baseline and vehicle control groups, suggesting that treatment was rescuing motor impairment in aged mice. The functional and biochemical readouts suggest that this small molecule has potential for treating neurodegenerative diseases characterized by tau aggregation such as AD and progressive supranuclear palsy.
    DOI:  https://doi.org/10.1111/jnc.70025
  8. Comput Biol Chem. 2025 Feb 28. pii: S1476-9271(25)00075-1. [Epub ahead of print]117 108415
    Nalidixic acid inhibits the aggregation of HSA: Utilizing the molecular simulations to uncover the detailed insights.
    Jihad Alrehaili, Razique Anwer, Faizan Abul Qais.
      Neurodegenerative diseases such as Parkinson's and Alzheimer's lead to the gradual decline of the nervous system, resulting in cognitive and motor impairments. With an aging population, the prevalence and associated healthcare costs are anticipated to rise. Misfolded protein aggregates are central to these diseases, disrupting cellular function and causing neuronal death. Preventing these toxic aggregates could preserve neurons and slow disease progression. Understanding how to inhibit protein aggregation is crucial for developing effective treatments. We explored the effect of nalidixic acid (NA) on protein aggregation using human serum albumin (HSA) as model protein. In vitro assays demonstrated that NA significantly reduced ThT fluorescence by 47.10 % and decreased turbidity by 63.07 %. NA also protected the protein's hydrophobic surfaces. The α-helical content of HSA dropped from 56.23 % to 11.43 % but was restored to 38.53 % with NA. We then utilized advanced molecular simulations to understand the kinetics and mechanism of aggregation inhibition by NA. Binding studies showed that NA attaches to HSA's subdomain IIA with a binding energy of -7.8 kcal/mol through hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Molecular simulations confirmed the stability of HSA-NA complex. Additionally, NA increased solvent accessibility of HSA282-292 oligomers, reduced hydrogen bonding, and prevented β-sheet formation. Compared to existing anti-aggregation strategies, NA offers a promising alternative with its potential therapeutic applications in neurodegenerative diseases by stabilizing protein structures and preventing misfolding. These findings highlight NA's potential as a candidate for inhibiting protein aggregation and offer insights for therapeutic approaches. Further experimental studies utilizing in vivo models are needed to validate the anti-aggregation potential of NA.
    Keywords:  Aggregation; Human serum albumin; Molecular dynamics simulation; Nalidixic acid; ThT fluorescence
    DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108415
  9. Int J Biol Macromol. 2025 Mar 01. pii: S0141-8130(25)02228-7. [Epub ahead of print]306(Pt 3): 141677
    Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances.
    Mei Dang, Longjiang Wu, Xiaoying Zhang.
      Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding protein involved in various cellular processes, including RNA splicing, transcription regulation, and RNA stability. Mislocalization and aggregation of TDP-43 in the cytoplasm are key features of the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). This review provides a comprehensive retrospective and prospective analysis of TDP-43 research, highlighting structural insights, significant milestones, and the evolving understanding of its physiological and pathological functions. We delineate five major stages in TDP-43 research, from its initial discovery as a pathological hallmark in neurodegeneration to the recent advances in understanding its liquid-liquid phase separation (LLPS) behavior and interactions with cellular processes. Furthermore, we assess therapeutic strategies targeting TDP-43 pathology, categorizing approaches into direct and indirect interventions, alongside modulating aberrant TDP-43 LLPS. We propose that future research will focus on three critical areas: targeting TDP-43 structural polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation of TDP-43, and advancing nano-therapy. More importantly, we emphasize the importance of understanding TDP-43's functional repertoire at the mesoscale, which bridges its molecular functions with broader cellular processes. This review offers a foundational framework for advancing TDP-43 research and therapeutic development.
    Keywords:  Neurodegenerative diseases; Therapeutic strategies; Transactive response (TAR) DNA-binding protein 43 (TDP-43)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141677
  10. Arch Toxicol. 2025 Mar 06.
    Potential role of ochratoxin A in Parkinson's disease: a systematic review of current evidence.
    M Serrano-Civantos, E Beraza, L Álvarez-Erviti, A López de Cerain, A Vettorazzi.
      Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species that contaminates various food and feed products, presenting potential risks to human health. While OTA is well-known for its nephrotoxic effects, emerging evidence highlights its neurotoxic potential. Parkinson's disease (PD) is a neurodegenerative disorder with both genetic and environmental aetiologies. Emerging lines of investigation have focused their research on the role of environmental toxins, including mycotoxins, in PD pathogenesis. However, the specific involvement of OTA in PD-related pathways still needs to be unravelled. This systematic review compiles and evaluates OTA neurotoxicity studies according to the adverse outcome pathway (AOP) for PD, established by the Organisation for Economic Cooperation and Development (OECD). The AOP framework outlines a series of key event (KEs) beginning with mitochondrial Complex I (CI) inhibition and progressing through mitochondrial dysfunction, impaired proteostasis, dopaminergic neuron degeneration, neuroinflammation, and resulting in parkinsonian motor deficits. In this systematic review, a comprehensive literature search was conducted in PubMed, to identify studies evaluating OTA neurotoxic effects. Using a search strategy of 19 terms and following a two-phased study selection, 30 relevant studies were retrieved, of which 16 dealt with in vitro adult neurotoxicity (ANT), 13 focused on in vivo ANT, and 1 gave both in vitro and in vivo approaches. Authors agree that in vitro and in vivo exposure to OTA causes mitochondrial dysfunction, impaired proteostasis, degeneration of dopaminergic (DA) neurons, and neuroinflammation. However, a notable absence of research remains on the molecular initiating event (MIE), binding to CI, and on KE1, inhibition of CI. This review identifies critical research gaps and highlights the need for further mechanistic studies on the impact of OTA on neurodegenerative pathways, particularly its binding and inhibition of CI, as well as mechanisms related to KE3: impaired proteostasis. Addressing these gaps may provide valuable insights into OTA neurotoxic potential and its relevance in PD-like neurodegeneration.
    Keywords:  Adverse outcome pathway; Neurodegeneration; Neurotoxicity; Ochratoxin; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s00204-025-03994-5
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