bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–09–28
sixteen papers selected by
Verena Kohler, Umeå University
  1. Tau Enhances Aggregation of S100A9 Protein and Further Association of Its Fibrils.
  2. Autophagy in Proteostasis AND AGING in C. ELEGANS.
  3. Interaction Between α-Synuclein and DJ-1 in Parkinson's Disease.
  4. Exogenous Huntingtin-Exon1 Aggregates Exhibit Distinct Levels of Toxicity to Caenorhabditis elegans.
  5. Stabilizing a Native Fold of Alpha-Synuclein with Short Helix-Constrained Peptides.
  6. Galectin-3 as a Key Driver of Neuroinflammation and α-Synuclein Aggregation in Parkinson's Disease: Unlocking New Paths for Biomarkers and Therapies.
  7. Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide.
  8. Zn2+ Binding Shifts the Conformational Ensemble of α-Synuclein Monomers toward Accelerated Amyloid Formation.
  9. Single Particle Dynamics of Protein Aggregation and Disaggregation in the Presence of the sHsp Proteins IbpAB.
  10. Determination of α-Synuclein Protein Interactions by μMap Photo-proximity Labeling.
  11. Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.
  12. Label-free detection of early-stage protein aggregation using a fiber-optic mechanical resonant probe.
  13. IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in Amyotrophic Lateral Sclerosis.
  14. The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's Disease.
  15. Direct Observation of the Conformational Transitions in Tau and Their Correlation with Phase Behavior.
  16. Inhibiting MARS attenuates hyperhomocysteinemia-associated neurodegeneration in Parkinson's disease.
  1. Int J Mol Sci. 2025 Sep 15. pii: 8961. [Epub ahead of print]26(18):
    Tau Enhances Aggregation of S100A9 Protein and Further Association of Its Fibrils.
    Lukas Krasauskas, Dominykas Veiveris, Mantas Žiaunys, Darius Šulskis, Andrius Sakalauskas, Vytautas Smirnovas.
      The formation and accumulation of amyloid fibrils is implicated as one of the main reasons for the onset and progression of several widespread neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Decades of effort to unravel the intricate mechanisms of amyloid aggregation have only led to limited success in developing potent treatment modalities. Generally, this failure is considered to be the result of our incomplete understanding of the processes governing protein transitions into these insoluble fibrillar structures. Recently, a growing number of studies have reported that multiple amyloidogenic proteins, including ones related to the most debilitating disorders, can cross-interact during aggregation. This process leads to different nucleation and fibril elongation rates, aggregate structures, and even their cytotoxicity. Despite this revelation, the entire amyloid interactome remains largely unexplored. In this work, we investigate the cross-interaction between the Alzheimer's disease-related Tau protein and a pro-inflammatory S100A9 protein, which has recently been implicated as a possible modulator of amyloid aggregation. We show that Tau 2N4R enhances the amyloid aggregation propensity of S100A9 and mediates the self-association of the resulting fibrils, demonstrating this pairing's potential role in the onset of neurodegenerative disorders.
    Keywords:  S100A9; Tau; aggregation; amyloid; cross-interaction
    DOI:  https://doi.org/10.3390/ijms26188961
  2. Cell Stress Chaperones. 2025 Sep 18. pii: S1355-8145(25)00060-4. [Epub ahead of print] 100115
    Autophagy in Proteostasis AND AGING in C. ELEGANS.
    Caitlin M Lange, Ryo Higuchi-Sanabria, Caroline Kumsta.
      Proteostasis (protein homeostasis), the balance of protein synthesis, folding, and degradation, is critical for cellular function and organismal health. Its disruption leads to the accumulation of misfolded and aggregated proteins, hallmarks of aging and age-related diseases including neurodegeneration. Autophagy, a conserved lysosome-mediated degradation pathway, is central to proteostasis by clearing toxic proteins and damaged organelles. In Caenorhabditis elegans, studies across conserved longevity paradigms and models of neurodegenerative diseases have defined key mechanisms by which autophagy maintains proteostasis during aging and stress. Beyond its degradative functions, autophagy contributes to spatial quality control by promoting the formation of potentially protective protein inclusions and coordinating with the ubiquitin-proteasome system. Emerging evidence also points to noncanonical autophagy pathways, such as unconventional secretion and inter-tissue communication, that broaden its role in systemic proteostasis. Together, these advances underscore autophagy's multifaceted contribution to protein quality control, with wide-ranging implications for aging, stress resistance and neurodegenerative disease.
    Keywords:  Aggresome; Aging; Autophagy; C. elegans; Inclusion body; Inter-tissue signaling; Longevity; Neurodegeneration; Protein Aggregation; Proteostasis; Secretion; Stress Response
    DOI:  https://doi.org/10.1016/j.cstres.2025.100115
  3. Brain Sci. 2025 Aug 22. pii: 899. [Epub ahead of print]15(9):
    Interaction Between α-Synuclein and DJ-1 in Parkinson's Disease.
    Pouya Sobhifar, David R Brown.
      Parkinson's disease (PD) is one of the most common neurodegenerative disorders among the elderly. The exact etiology of sporadic PD is still unknown; however, there is general consensus that the accumulation and aggregation of α-synuclein (α-syn) are among the prominent pathological features. The precise function of α-syn in the healthy human brain is not agreed upon, although it has been reported to play a role in vesicular trafficking and neurotransmitter release. Dutch Juvenile-1 (DJ-1) is a multifunctional protein involved in regulating an array of mechanisms, including oxidative stress, ferroptosis, mitochondrial and dopamine homeostasis. Loss-of-function of DJ-1 was reported to cause familial PD, and oxidative inactivation of DJ-1 has been observed in sporadic cases, suggesting that both genetic and post-translational events converge on common disease pathways. This review proposes that loss of DJ-1 function may elevate intracellular α-syn levels, leading to their aggregation and consequent neurotoxicity. Reports suggest that DJ-1 can inhibit α-syn aggregation, facilitate α-syn clearance via chaperone-mediated autophagy, and act as a deglycase or glyoxalase to neutralize glycated α-syn species. Clinical studies have also reported altered DJ-1 oxidation states in PD patient samples, supporting its potential as a biomarker. By bridging familial and sporadic PD mechanisms, DJ-1 emerges as a compelling therapeutic target with the potential to mitigate α-syn-mediated neurodegeneration across both forms. However, further research is required to fully establish its clinical relevance and translational potential.
    Keywords:  DJ-1; Parkinson’s disease; aggregation; glycation; α-synuclein
    DOI:  https://doi.org/10.3390/brainsci15090899
  4. ACS Chem Neurosci. 2025 Sep 23.
    Exogenous Huntingtin-Exon1 Aggregates Exhibit Distinct Levels of Toxicity to Caenorhabditis elegans.
    Ephraim Ezeigbo, Kaitlyn Keith, Zachary L Ellis, Korina Pebley, Tyler Girman, Anjola Adewoye, Alyssa R Stonebraker, Pritom Kumar Biswas, Justin Legleiter.
      Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD), are associated with proteinaceous deposits in the brain comprising amyloid. The aggregation process leading to these deposits proceeds through a variety of intermediates, i.e., oligomers and fibrils. The heterogeneity of aggregates produced complicates the assignment of specific toxic functions to distinct aggregate species. Here, a simple centrifugation strategy was employed to produce well-characterized and relatively homogeneous populations of huntingtin (htt) aggregates in vitro. After characterization of the resulting aggregate populations, C. elegans were exogenously exposed to these different aggregates species to assess their impact on worm viability. Htt oligomers were identified as the most acutely toxic aggregate form. Nonaggregated htt and fibrils did not significantly reduce C. elegans viability. A variety of methods to manipulate htt oligomers were then tested to demonstrate the ability to modify oligomer toxicity in this model system. Chemically cross-linking htt oligomers reduced their toxicity, suggesting that structural flexibility is important in oligomer toxicity. Stabilizing oligomers with truncated peptides based on the first 17 N-terminal amino acids (Nt17) impacted toxicity when specific acetylation-mimicking point mutations were introduced. Nt17-derived peptides without any mutations did not alter toxicity; however, the addition of acetylation-mimicking mutations toward the C-terminus of the peptide reduces toxicity. Finally, two small molecules that modify htt aggregation, EGCG and riluzole, were tested for their impact on oligomer toxicity. In general, this approach provides a simple method to investigate and manipulate the toxicity of aggregate subpopulation in a quasi-controlled manner.
    Keywords:  Huntington’s disease; amyloid fibrils; neurodegenerative disease; oligomers; polyglutamine; protein aggregation
    DOI:  https://doi.org/10.1021/acschemneuro.5c00513
  5. JACS Au. 2025 Sep 22. 5(9): 4321-4336
    Stabilizing a Native Fold of Alpha-Synuclein with Short Helix-Constrained Peptides.
    Richard M Meade, Scott G Allen, Amy J Lopez, Christopher Williams, Iona Thomas-Wright, Rachel Heon-Roberts, Mara Carey-Wood, T M Simon Tang, Julia E Sero, Vicky L Hunt, Richard Wade-Martins, Matthew P Crump, Jody M Mason.
      Preventing the aggregation of α-synuclein (αS) into toxic oligomers and conformers is a major therapeutic goal in conditions such as Parkinson's disease and Lewy body dementia. However, the large intracellular protein-protein interfaces within such aggregates make this a challenging target for small molecule approaches or biologics, which often lack cell permeability. Peptides occupy a suitable middle ground and are increasingly being explored as preventative treatments. We previously showed that the N-terminal lipid binding region (αS1-25) inhibits αS aggregation. Building on this, we designed a series of N- and C-terminal truncations to systematically reduce the peptide length, enabling a 56% downsizing (i.e., truncating 92% of the full-length αS protein), to identify the smallest functional unit capable of binding αS and potently blocking its aggregation and toxicity. We next introduced seven systematic i → i + 4 helix constraints to assess impact on (i) α-helicity, (ii) aggregation inhibition, (iii) serum stability, (iv) neuronal uptake, and (v) phenotypic rescue. This work maps key amphipathic features and identifies residues that are critical for αS engagement and inhibitory activity. The most effective helix-constrained peptide, αS2-12(L6), showed marked improvements across all metrics and represents a strong candidate for further therapeutic development.
    Keywords:  Parkinson’s disease; amyloid aggregation; lipid induced aggregation; lipid vesicles; peptide
    DOI:  https://doi.org/10.1021/jacsau.5c00694
  6. Cell Biochem Biophys. 2025 Sep 27.
    Galectin-3 as a Key Driver of Neuroinflammation and α-Synuclein Aggregation in Parkinson's Disease: Unlocking New Paths for Biomarkers and Therapies.
    Pratyush Porel, Gulam Varish, Khadga Raj Aran.
      
    Keywords:  Biomarker; Galectin-3; Neuroinflammation; Parkinson’s disease; Therapeutic target; Α-Synuclein
    DOI:  https://doi.org/10.1007/s12013-025-01875-3
  7. NPJ Parkinsons Dis. 2025 Sep 22. 11(1): 271
    Direct disassembly of α-syn preformed fibrils into α-syn monomers by an all-D-peptide.
    Marc Sevenich, Ian Gering, Bettina Kass, Madita Vollmer, Selma Aghabashlou Saisan, Markus Tusche, Tatsiana Kupreichyk, Thomas Pauly, Matthias Stoldt, Wolfgang Hoyer, Antje Willuweit, Janine Kutzsche, Nils-Alexander Lakomek, Luitgard Nagel-Steger, Lothar Gremer, Gültekin Tamgüney, Jeannine Mohrlüder, Dieter Willbold.
      A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration associated with soluble oligomeric and fibrillar forms of misfolded α-synuclein (α-syn). In this study, all-D-enantiomeric peptide ligands are presented that bind monomeric α-syn with high affinity, stabilize its physiological monomeric status, prevent aggregation and dissolve existing aggregates. This "antiprionic" mode of action directly targets pathogenic aggregated particles. Using mirror-image phage display on D-enantiomeric full-length α-syn, SVD-1 and SVD-1a were identified, showing a delay of aggregation and reduction of aggregate formation in both de novo and seeded models. Picomolar KDs were confirmed by SPR, where a highly dynamic interaction mode was verified by PRE-NMR. SVD-1a also reduced the toxicity and intracellular seeding of α-syn fibrils in cell culture by disassembling them into monomers, as confirmed by atomic force microscopy and dynamic light scattering. These results support SVD-1a as a promising lead compound for the treatment of Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41531-025-01132-7
  8. J Am Chem Soc. 2025 Sep 25.
    Zn2+ Binding Shifts the Conformational Ensemble of α-Synuclein Monomers toward Accelerated Amyloid Formation.
    Emily J Byrd, Benjamin Rowlinson, Joel A Crossley, David J Brockwell, James F Ross, Sheena E Radford, Frank Sobott.
      Alpha-synuclein (αS) is an intrinsically disordered protein (IDP) that can self-assemble into amyloid fibrils, undergoing a transition from disordered monomers to ordered β-sheet-rich fibrils. The amyloid state of αS is implicated in various synucleinopathies, most notably Parkinson's disease (PD), in which αS fibrils accumulate as insoluble Lewy body deposits. Colocalized with αS in Lewy bodies are elevated levels of metal ions including Zn2+. We find in vitro that Zn2+ accelerates aggregation of N-terminally acetylated αS, decreasing the t50 ca. 5-fold, as measured by thioflavin T (ThT) fluorescence. Strikingly, the extent of Zn2+ binding (native mass spectrometry; MS) and shifts of the monomeric αS conformational ensemble toward compaction, measured using ion mobility MS (IM-MS) at different αS:Zn2+ ratios, mirror precisely the accelerated aggregation kinetics. Chemical shift perturbations in Nuclear Magnetic Resonance (NMR) spectroscopy were investigated together with molecular dynamics (MD) to map the Zn2+ binding sites and subsequent effects on conformation under identical solution conditions to those used in IM-MS. Zn2+ is found to predominantly interact with negative residues in the C-terminal region of αS but also His50 in the N-terminal region. This promiscuity in interactions potentially guides compaction of the protein chain by bridging residues between the N- and C-terminal regions through Zn2+ ion co-ordination. This study provides insights into the early stages of amyloid assembly, correlating aggregation kinetics with structural compaction in monomeric αS and highlighting the capability of native IM-MS to resolve complex structural ensembles of a disordered protein.
    DOI:  https://doi.org/10.1021/jacs.5c11056
  9. Biochemistry. 2025 Sep 26.
    Single Particle Dynamics of Protein Aggregation and Disaggregation in the Presence of the sHsp Proteins IbpAB.
    Andrew Roth, YuChen Yang, Jason Puchalla, Hays S Rye.
      The small heat shock proteins (sHsps) are a key class of molecular chaperones that can inhibit protein aggregation and enhance protein recovery from aggregates. However, the mechanisms sHsps employ to carry out these roles are not well understood, in part because the highly heterogeneous and dynamic particles they form with aggregating proteins are difficult to study with traditional biophysical tools. Here we have applied a novel single particle fluorescence technique known as Burst Analysis Spectroscopy (BAS) to the study of the Escherichia coli sHsps IbpA and IbpB (IbpAB). We show that in the presence of IbpAB, two different model proteins converge toward similar, limited aggregate particle size distributions. Additionally, while IbpAB dramatically accelerates the disassembly of protein aggregates by the bacterial KJEB bichaperone disaggregase, this enhancement does not appear to be strongly influenced by aggregate particle size. Rather, it is the ability of IbpAB to alter aggregate structure during particle formation that appears to be essential for stimulated disassembly. These observations support a model of aggregate recognition by IbpAB that is not only highly adaptable but capable of shaping aggregate particles into a specialized range of physical properties that are necessary for efficient protein disaggregation.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00312
  10. bioRxiv. 2025 Sep 18. pii: 2025.09.18.674129. [Epub ahead of print]
    Determination of α-Synuclein Protein Interactions by μMap Photo-proximity Labeling.
    Marshall G Lougee, Grace S H Park, Hee Jong Kim, Jiya Z Fowler, Zongtao Lin, Hossein Fazelinia, Lynn Spruce, Evan Yanagawa, Benjamin A Garcia, Melike Lakadamyali, E James Petersson.
      Fibrillar aggregates of the natively disordered protein α-synuclein (αS) are hallmarks of Parkinson's disease and related neurodegenerative disorders termed synucleinopathies. Here, we used micromap (µMap) photo-proximity labeling to determine the interactomes of αS monomers and fibrils in mouse brain lysate to better understand both the loss of healthy function and gain of toxic function aspects of synucleinopathies. Several αS variants were synthesized and characterized, showing that the small size (1 kDa) of the Ir catalyst attached through a Cys-maleimide linkage makes it minimally-perturbing to αS, with a narrow labeling radius that allows one to identify interactome differences between different regions of αS. Monomer and fibril interactomes were compared to each other and to previous proximity labeling data sets for validation and several examples of further investigations are demonstrated, including Western blotting, super-resolution microscopy, and µMap in primary neurons.
    DOI:  https://doi.org/10.1101/2025.09.18.674129
  11. Biomolecules. 2025 Aug 25. pii: 1221. [Epub ahead of print]15(9):
    Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.
    Zhengming Tian, Feiyang Jin, Zhuowen Geng, Zirui Xu, Qianqian Shao, Guiyou Liu, Xunming Ji, Jia Liu.
      Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.
    Keywords:  acute/chronic neurodegenerative diseases; aging; cerebral hemoglobin; circulating hemoglobin; hypoxia; non-oxygen-binding functionality
    DOI:  https://doi.org/10.3390/biom15091221
  12. Opt Express. 2025 Sep 08. 33(18): 38803-38813
    Label-free detection of early-stage protein aggregation using a fiber-optic mechanical resonant probe.
    Yuliang Liu, Guifeng Li, Guoquan Wang, Zhonghao Li, Chaoyang Gong, Tao Zhu.
      Early detection of protein aggregates offers valuable insights into the pathophysiology of a variety of neurodegenerative diseases. However, fluorescence methods, which serve as the "golden standard" for detecting protein aggregation, rely on fluorophores that bind to aggregated proteins, potentially interfering with the aggregation process. Here, we propose a fiber-optic mechanical resonant probe (FOMRP) for the label-free detection of early-stage protein aggregation by monitoring the mechanical properties of the protein solution. The FOMRP was fabricated by a tapered optical fiber and was driven by a piezoelectric actuator. The mechanical vibration of FOMRP was monitored with a fiber Bragg grating. We found that the FOMRP supports a series of nonlinear mechanical vibrations. We investigated the energy transfer mechanism between the fundamental and harmonic vibration modes. The 1/2 order subharmonic vibration was found to be highly sensitive to the external environment and was subsequently employed for viscosity measurement. The FOMRP was further applied to monitor early-stage protein aggregation, showing higher sensitivity than the conventional fluorescence method. This approach provides a promising tool for label-free protein aggregation monitoring and has potential applications in molecular and cellular mechano-assays.
    DOI:  https://doi.org/10.1364/OE.571612
  13. J Biol Chem. 2025 Sep 24. pii: S0021-9258(25)02616-X. [Epub ahead of print] 110764
    IRE1/Xbp1 promotes the clearance of poly(GR) dipeptide repeats in Amyotrophic Lateral Sclerosis.
    Yu Li, Dongyue Liu, Shuangxi Li.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by the expansion of GGGGCC (G4C2) repeats in the C9orf72 gene and progressive motor neuron degeneration. A key pathological hallmark of these diseases is the accumulation and cytoplasmic mislocalization of dipeptide repeat (DPR) proteins, particularly poly(GR), which are neurotoxic. Enhancing the clearance of poly(GR) represents a promising therapeutic strategy; however, the molecular mechanisms regulating poly(GR) turnover are not fully understood. Our previous work demonstrated that translationally stalled poly(GR) is targeted by the ribosome-associated quality control (RQC) pathway. In the present study, we identify the IRE1/Xbp1s signaling axis as an essential regulator of poly(GR) degradation. Ectopic expression of IRE1 or its downstream effector Xbp1s, as well as pharmacological activation of IRE1 using IXA4, significantly reduces poly(GR) protein levels in a Drosophila disease model, mammalian cell lines, fibroblasts derived from C9orf72-ALS patients, and a C9orf72 transgenic mouse model. Mechanistically, RNA-sequencing analysis reveals that IRE1/Xbp1s signaling upregulates heat shock protein Hsp70Ba, which plays a critical role in maintaining poly(GR) proteostasis. Additionally, we show that the Rictor/AKT/VCP pathway contributes to the translational regulation and turnover of poly(GR). Importantly, activation of IRE1, either through ectopic expression or IXA4 treatment, mitigates motor neuron loss in the C9orf72 mouse model. Collectively, our findings highlight the IRE1/Xbp1s axis as a key modulator of poly(GR) clearance and suggest its therapeutic potential in ALS/FTD.
    Keywords:  Drosophila melanogaster; IRE1; Xbp1; poly(GR)
    DOI:  https://doi.org/10.1016/j.jbc.2025.110764
  14. bioRxiv. 2025 Sep 17. pii: 2025.09.16.676664. [Epub ahead of print]
    The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's Disease.
    Thomas A Shoff, Maxence Derbez-Morin, Peishan Cai, Ryan R Julian.
      Alzheimer's disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid β (Aβ) and tau, yet existing models of AD fail to provide a simple connection between Aβ and tau. However, microtubules provide an intriguing nexus for pathological interactions between the two. Tau binds to microtubules and is critical to maintain their proper function. We demonstrate that Aβ also binds to microtubules with affinity comparable that of tau itself. We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of Aβ is not the primary cause of toxicity, which allows many of the apparent contradictions between Aβ pathology and cognition to be rationalized. This new model highlights the importance of both tau and Aβ and enables novel therapeutic and intervention strategies to be considered.
    DOI:  https://doi.org/10.1101/2025.09.16.676664
  15. JACS Au. 2025 Sep 22. 5(9): 4268-4280
    Direct Observation of the Conformational Transitions in Tau and Their Correlation with Phase Behavior.
    Jitao Wen, Yiming Tang, Tomas Sneideris, Hannes Ausserwöger, Liu Hong, Tuomas P J Knowles, Sarah Perrett, Guanghong Wei, Si Wu.
      Liquid-liquid phase separation (LLPS) is now recognized as one of the key mechanisms underlying the formation of membraneless organelles. Typically, condensates formed through LLPS are dynamic and play a crucial role in the spatiotemporal regulation of essential cellular processes. In some cases, however, condensates can undergo an aberrant liquid-to-solid transition, which is now recognized as being related to the onset of cancers and neurodegeneration. The microtubule-associated protein Tau, the aberrant aggregation of which is implicated in neurodegenerative disorders like Alzheimer's and Parkinson's, has been found to undergo LLPS. The Tau condensates formed through LLPS are considered to be intermediate on-pathway precursors of amyloid aggregates. Unlike other known phase-separating proteins (e.g., FUS or TDP-43) that have low-complexity domains (LCDs), Tau is intrinsically disordered. Thus, Tau exhibits a highly flexible structure that can be modulated by changes in environmental changes. The intricate relationship between different conformations of full-length Tau and its phase behavior remains poorly understood. To bridge this gap, here, by employing a combination of single-molecule FRET and molecular dynamics simulations, we demonstrate that Tau undergoes conformational transitions from compact to extended states during LLPS, irrespective of diverse driving forces. Moreover, we show that intramolecular interactions responsible for stabilizing the compact conformations of monomeric Tau correlate with the intermolecular interactions driving the LLPS of Tau, thereby facilitating the formation of dynamic networks. These findings provide crucial mechanistic insights into how the conformational state of Tau governs its propensity for phase separation, shedding light on sequence-encoded structural processes that ultimately drive biological phase separation.
    Keywords:  conformational dynamics; intrinsically disorder proteins; liquid−liquid phase separation; molecular dynamics simulations; single-molecule FRET
    DOI:  https://doi.org/10.1021/jacsau.5c00625
  16. Neuropharmacology. 2025 Sep 23. pii: S0028-3908(25)00393-4. [Epub ahead of print] 110685
    Inhibiting MARS attenuates hyperhomocysteinemia-associated neurodegeneration in Parkinson's disease.
    Tao Guo, Dandan Su, Juan Huang, Guohua Zhao, Xin Fang, Ting Yu, Shangqi Sun, Anyu Bao, Lihong Bu, Zhentao Zhang.
      Hyperhomocysteinemia is an independent risk factor for Parkinson's disease (PD). Homocysteine (Hcy) is converted to Hcy thiolactone (HTL) in error-editing reactions catalyzed by methionine-tRNA synthetase (MARS). HTL forms isopeptide bonds with lysine residues of target proteins in a process known as N-homocysteinylation (N-Hcy), which contributes to the neurotoxicity of Hcy in PD pathogenesis. Thus, MARS may represent a potential target for controlling hyperhomocysteinemia-associated neurotoxicity. Here we tested the effect of MARS on protein N-Hcy in cultured cells, MPTP-induced mouse model of PD, and mice injected with α-synuclein PFFs. We found that the protein N-Hcy levels were increased in the brains of PD model mice. MARS knockdown ameliorates protein N-Hcy, oxidative stress, mitochondrial dysfunction, and α-synuclein aggregation in cells. MARS knockdown also alleviated dopaminergic neurodegeneration and behavioral deficits in mice injected with MPTP. In mice injected with α-synuclein fibrils, MARS knockdown attenuated α-synuclein aggregation, dopaminergic neurodegeneration, and motor impairments. These results indicate that inhibition of MARS attenuates PD-like pathology induced by hyperhomocysteinemia.
    Keywords:  Methionine-tRNA synthetase; N-homocysteinylation; homocysteine; oxidative stress; α-synuclein
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110685
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