bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–03–30
seven papers selected by
Verena Kohler, Umeå University
  1. Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease.
  2. Tau Oligomers Resist Phase Separation.
  3. Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation.
  4. Emerging biophysical origins and pathogenic implications of amyloid oligomers.
  5. A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.
  6. Dual modulation of amyloid beta and tau aggregation and dissociation in Alzheimer's disease: a comprehensive review of the characteristics and therapeutic strategies.
  7. Concentration-Based Analysis of Metal-Induced Tau Fibrillar versus non-fibrillar Aggregation: Implications for Neurotoxicity in Alzheimer's Disease.
  1. Cell Mol Neurobiol. 2025 Mar 26. 45(1): 30
    Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease.
    Shakila Yaribash, Keyhan Mohammadi, Mahmood Alizadeh Sani.
      Worldwide aging has contributed to the growth of prevalence of neurodegenerative diseases (NDDs), including Parkinson's disease among the elderlies. The advanced destruction of dopaminergic neurons in the substantia nigra, due to many accelerator factors in the brain is the main mechanism of Parkinson's disease. The pathological aggregated alpha-synuclein (α-syn), a protein implicated in multiple neurodegenerative disorders, is one of the critical factors in this neurodegenerative disease and other similar disorders. The misfolding and aggregation of α-syn may interrupt critical processes, including functions of synaptic vesicles and can lead to neuronal death. This protein is encoded by Alpha-Synuclein Gene (SNCA) and mutation in this gene can lead to dysfunctions of the protein structure. Since, therapeutic policies that aim α-syn are promising approaches. Advances in immunotherapies, molecular chaperones, gene therapy targeting SNCA, and DNA aptamers are some examples of this strategy. This review aims to comprehensively assess the current knowledge and evidence on α-syn pathology, genetic determinants, and novel therapeutic methods in Parkinson,'s disease and other synucleinopathies. Continued investigation to discover interventions in this system could result in finding of effective and safe treatments for NDDs.
    Keywords:  Alpha- synucleinopathy; Alpha-synuclein; Neurodegenerative diseases; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s10571-025-01544-2
  2. Biomolecules. 2025 Feb 26. pii: 336. [Epub ahead of print]15(3):
    Tau Oligomers Resist Phase Separation.
    Lathan Lucas, Phoebe S Tsoi, Josephine C Ferreon, Allan Chris M Ferreon.
      Tau is a microtubule-associated protein that undergoes liquid-liquid phase separation (LLPS) to form condensates under physiological conditions, facilitating microtubule stabilization and intracellular transport. LLPS has also been implicated in pathological Tau aggregation, which contributes to tauopathies such as Alzheimer's disease. While LLPS is known to promote Tau aggregation, the relationship between Tau's structural states and its phase separation behavior remains poorly defined. Here, we examine how oligomerization modulates Tau LLPS and uncover key distinctions between monomeric, oligomeric, and amyloidogenic Tau species. Using dynamic light scattering and fluorescence microscopy, we monitored oligomer formation over time and assessed oligomeric Tau's ability to undergo LLPS. We found that Tau monomers readily phase separate and form condensates. As oligomerization progresses, Tau's propensity to undergo LLPS diminishes, with oligomers still being able to phase separate, albeit with reduced efficiency. Interestingly, oligomeric Tau is recruited into condensates formed with 0-day-aged Tau, with this recruitment depending on the oligomer state of maturation. Early-stage, Thioflavin T (ThT)-negative oligomers co-localize with 0-day-aged Tau condensates, whereas ThT-positive oligomers resist condensate recruitment entirely. This study highlights a dynamic interplay between Tau LLPS and aggregation, providing insight into how Tau's structural and oligomeric states influence its pathological and functional roles. These findings underscore the need to further explore LLPS as a likely modulator of Tau pathogenesis and distinct pathogenic oligomers as viable therapeutic targets in tauopathies.
    Keywords:  LLPS; neurodegeneration; tau oligomers; tau pathology; tauopathy
    DOI:  https://doi.org/10.3390/biom15030336
  3. Sci Rep. 2025 Mar 25. 15(1): 10283
    Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation.
    Masumi Sugiyama, Kenneth S Kosik, Eleni Panagiotou.
      Recent studies of tau proteins point to specific sites or motifs along the protein related to its misfolding and aggregation propensity, which is associated with neurodegenerative diseases of structure-dependent pathology. In this manuscript we employ topology and geometry to analyze the local structure of tau proteins obtained from the Protein Data Bank. Our results show that mathematical topology/geometry of cryo-EM structures alone identify the PGGG motifs, and the PHF6(*) motifs as sites of interest and reveal a geometrical hierarchy of the PGGG motifs that differs for 3R+4R and 4R tauopathies. By employing the Local Topological Free Energy (LTE), we find that progressive supranuclear palsy (PSP) and globular glial tauopathy (GGT) have the highest LTE values around residues 302-305, which are inside the jR2R3 peptide and in the vicinity of the 301 site, experimentally associated with aggregation. By extending the LTE definition to estimate a global topological free energy, we find that the jR2R3 peptide of PSP and GGT, has in fact the lowest global topological free energy among other tauopathies. These results point to a possible correlation between the global topological free energy of parts of the protein and the LTE of specific sites.
    Keywords:  Aggregation; Geometry; Neurodegenerative disease; Structure; Tau protein; Topology
    DOI:  https://doi.org/10.1038/s41598-025-93304-x
  4. Nat Commun. 2025 Mar 26. 16(1): 2937
    Emerging biophysical origins and pathogenic implications of amyloid oligomers.
    Huayuan Tang, Nicholas Andrikopoulos, Yuhuan Li, Stone Ke, Yunxiang Sun, Feng Ding, Pu Chun Ke.
      The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer's and Parkinson's disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and β-barrel formation, their routes to neurodegeneration, and their role in cerebrovascular perturbation. Together, this Perspective converges on the multifaceted oligomer-axis central to the pathological origin and, hence, the treatment of amyloid diseases.
    DOI:  https://doi.org/10.1038/s41467-025-58335-y
  5. J Fungi (Basel). 2025 Feb 28. pii: 188. [Epub ahead of print]11(3):
    A Twist in Yeast: New Perspectives for Studying TDP-43 Proteinopathies in S. cerevisiae.
    Roberto Stella, Alessandro Bertoli, Raffaele Lopreiato, Caterina Peggion.
      TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer's disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases.
    Keywords:  ALS; RNA metabolism; TDP-43; autophagy; chaperone; mitochondrial dysfunction; neurodegeneration; nucleolin; protein aggregation; yeast
    DOI:  https://doi.org/10.3390/jof11030188
  6. Transl Neurodegener. 2025 Mar 26. 14(1): 15
    Dual modulation of amyloid beta and tau aggregation and dissociation in Alzheimer's disease: a comprehensive review of the characteristics and therapeutic strategies.
    Yunkwon Nam, Soo Jung Shin, Vijay Kumar, Jihyeon Won, Sujin Kim, Minho Moon.
      Alzheimer's disease (AD) is not a single-cause disease; rather, it is a complex neurodegenerative disease involving multiple pathological pathways influenced by various risk factors. Aggregation and accumulation of amyloid beta (Aβ) and tau are the most prominent features in the brains of AD patients. Aggregated Aβ and tau exert neurotoxic effects in the central nervous system, contributing to the pathogenesis and progression of AD. They also act synergistically to cause neurodegeneration, resulting in memory loss. In this context, dual inhibition of Aβ and tau aggregation, or dissociation of these two aggregates, is considered promising for AD treatment. Recently, dual inhibitors capable of simultaneously targeting the aggregation and dissociation of both Aβ and tau have been investigated. Specific amino acid domains of Aβ and tau associated with their aggregation/dissociation have been identified. Subsequently, therapeutic agents that prevent aggregation or promote disaggregation by targeting these domains have been identified/developed. In this review, we summarize the major domains and properties involved in Aβ and tau aggregation, as well as the therapeutic effects and mechanisms of agents that simultaneously regulate their aggregation and dissociation. This comprehensive review may contribute to the design and discovery of next-generation dual-targeting drugs for Aβ and tau, potentially leading to the development of more effective therapeutic strategies for AD.
    Keywords:  Aggregation; Alzheimer’s disease; Amyloid beta; Dissociation; Dual-targeting drugs; Tau
    DOI:  https://doi.org/10.1186/s40035-025-00479-4
  7. ChemistryOpen. 2025 Mar 24. e202400493
    Concentration-Based Analysis of Metal-Induced Tau Fibrillar versus non-fibrillar Aggregation: Implications for Neurotoxicity in Alzheimer's Disease.
    Mahzad Irandoust, Afrooz Anbaraki, Zahra Dindar, Atiyeh Ghasemi, Ali Akbar Saboury, Saeed Rayati, Arefeh Seyedarabi.
      Tau protein aggregation is the most significant factor in Alzheimer's disease (AD) pathogenesis, and the accumulation of metal ions in the brain is considered a key factor in the development of this disease. Tau protein exhibits two distinct aggregate structures: fibrillar and non-fibrillar aggregates. In this study, we conducted the first detailed study of the interactions of tau protein with three different concentrations of Zn2+, Cu2+, and Fe3+ions. Our findings demonstrate that low concentrations (0.01 mM) of these metal ions promote tau fibrillation, while higher concentrations (1 mM) induce non-fibrillar aggregates. We have investigated the structural changes of tau by using advanced techniques such as SDS-PAGE, DTNB, AFM, CD and fluorescence spectroscopy. At low concentrations, Zn2+ ions produced shorter fibrils, whereas Cu2+ and Fe3+ ions resulted in longer fibrils. CD showed increased β-sheet structures with a decrease in random coil content. Interestingly, Cu2+ ions caused a significant decrease in neuronal viability. Our data highlights a new approach that illuminates the different ways in which the metal ions distinctively cause tau fibrillar versus non-fibrillar aggregates, linked to neurotoxicity and neurodegeneration.
    Keywords:  Aggregation; Cytotoxicity; Fibrillation; Metal ions; Tau protein
    DOI:  https://doi.org/10.1002/open.202400493
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