bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2026–05–31
sixteen papers selected by
Verena Kohler, Umeå University
  1. Liquid-liquid phase separation and amyloid aggregation in the 14-3-3 protein family.
  2. Synaptic Vesicle Architecture Modulates α-Synuclein Conformation and Pathogenic Transitions in Parkinson's Disease.
  3. Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models.
  4. Biophysical assessment of the molecular mechanisms of Tau aggregation and its role in Alzheimer's disease.
  5. p53 regulates mitochondrial function and alpha-synuclein aggregation in Parkinson's disease.
  6. Local Organization of Biological Membranes Modulates Tau-Lipid Interactions and Fibril formation.
  7. Epigenetic Evidence Implies Disturbed Proteostasis and Potentially Protein Aggregation in Suicidality.
  8. Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.
  9. Early α-Synuclein Heterodimerization Kinetics Predict Parkinson's Disease Onset.
  10. Protein Modifications and Quality Control System: Target for Alzheimer's Disease Therapy.
  11. Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
  12. Lysophospholipids in Synucleinopathies: A Conceptual Framework Linking Proteostasis and Neuroinflammatory Signaling.
  13. Homocysteine increases phosphorylation and aggregation of α-synuclein.
  14. Mapping Hofmeister cation and anion effects on seeded and unseeded aggregation of TDP-43 and amyloid-β in micelle-assisted seed amplification.
  15. TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
  16. A β-hairpin mimic built on a fluorinated isoxazoline-β2,2-amino acid as a modulator of Tau protein aggregation.
  1. Int J Biol Macromol. 2026 May 23. pii: S0141-8130(26)02587-0. [Epub ahead of print]368 152660
    Liquid-liquid phase separation and amyloid aggregation in the 14-3-3 protein family.
    Saulė Rapalytė, Viktorija Karalkevičiūtė, Ieva Baronaitė, Dominykas Veiveris, Vytautas Smirnovas, Mantas Žiaunys, Darius Šulskis.
      The 14-3-3 protein family, with over 1300 binding partners, is one of the largest regulators of protein-protein interactions (PPIs) in eukaryotic cells. They recognise and bind to phosphorylation-related motifs in their partner proteins, creating scaffolds to stabilise proteins and allowing or inhibiting kinases' access to their targets. 14-3-3 consists of seven isoforms (β, γ, ε, ζ, η, θ and σ), which are expressed across all tissues. Given their important role in PPIs, their dysregulation can contribute to a variety of diseases, such as cancer or neurodegenerative disorders like Creutzfeldt-Jakob's, Parkinson's or Alzheimer's diseases. Pathological effects can arise due to loss of function, aberrant interactions or protein aggregation. Notably, 14-3-3 aggregates have been detected in Lewy bodies or cerebrospinal fluid, mirroring the presence of amyloid proteins, such as α-synuclein (α-syn) or β-amyloid. Toxic amyloid aggregation signals the onset of neurodegeneration, which can occur through misfolding of proteins or liquid-liquid phase separation (LLPS) - a process during which proteins condense into membraneless organelles. Unlike other amyloidogenic proteins, there is little information on the conditions under which the 14-3-3 protein family members undergo LLPS or their relationship with amyloid aggregation. To address this gap, we examined all isoforms of 14-3-3 in vitro and observed the formation of amyloid aggregates, phase-separated droplets and spheroid-like structures. Our results revealed that the ε and θ isoforms form amyloid-like fibrils that can accelerate α-syn aggregation. Furthermore, molecular crowding conditions promoted phase separation and aggregation in most 14-3-3 proteins. Finally, 14-3-3s incorporated together with α-syn generate heterotypical droplets.
    Keywords:  Amyloid; LLPS; Proteins
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152660
  2. Biosci Rep. 2026 May 29. pii: BSR20260364. [Epub ahead of print]
    Synaptic Vesicle Architecture Modulates α-Synuclein Conformation and Pathogenic Transitions in Parkinson's Disease.
    Priyatosh Ranjan.
      α-Synuclein (α-Syn) is a presynaptic protein that regulates synaptic vesicle organization, SNARE complex assembly, and neurotransmitter release through reversible interactions with curved lipid membranes. Increasing evidence indicates that α-Syn functions as a curvature-sensitive membrane adaptor whose N-terminal amphipathic helices selectively recognize the nanoscale architecture of synaptic vesicles, thereby promoting vesicle tethering, clustering, and membrane fusion dynamics essential for synaptic transmission. Recent structural and biophysical studies demonstrate that synaptic vesicles act as catalytic platforms in which membrane curvature, lipid packing defects, molecular crowding, and local physicochemical conditions determine whether α-Syn remains membrane-bound or transitions into pathogenic assemblies. Post-translational modifications, including phosphorylation, nitration, acetylation, and ubiquitination, dynamically regulate α-Syn conformation, membrane engagement, proteostatic turnover, aggregation propensity, and intracellular localization by modulating its structural plasticity and interactions with synaptic membranes. These modifications can alter electrostatic interactions, destabilize amphipathic helices, and shift α-Syn from functional membrane-associated states toward soluble oligomeric and amyloidogenic species. Aging further exacerbates these transitions through alterations in synaptic vesicle lipid composition, membrane fluidity, oxidative membrane damage, impaired proteostasis, and defective vesicle trafficking, thereby destabilizing α-Syn-membrane interactions. This Review discusses how membrane remodeling, vesicle lipid composition, post-translational modifications, protein conformational dynamics, and aging collectively regulate α-Syn phase behavior, membrane binding, and pathological aggregation at the presynaptic terminal. Integrating structural biology, lipidomics, proteomics, and live-cell imaging approaches will identify mechanistic transitions linking physiological membrane engagement to neurodegenerative synucleinopathies and reveal therapeutic opportunities for preventing synaptic dysfunction, toxic condensate formation, and neurodegeneration in Parkinson's disease and related disorders associated with pathological α-Syn aggregation.
    Keywords:  SNARE complex assembly; amyloid; intrinsically disordered proteins; random coil-helix transition; synaptic vesicle; synucleinopathies
    DOI:  https://doi.org/10.1042/BSR20260364
  3. Aging Cell. 2026 Jun;25(6): e70566
    Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models.
    Tariq T Ali, Anton Zhornyak, Madiha Merghani, Zora Buschenlange, Eri Sakata, Tiago F Outeiro, Blagovesta Popova, Gerhard H Braus.
      Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the aggregation of alpha-synuclein (αSyn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of αSyn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin-proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of αSyn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The αSyn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on αSyn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces αSyn aggregation and enhances αSyn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric αSyn in vitro. Notably, capped proteasomes retain proteolytic activities in the presence of αSyn, indicating resistance to αSyn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulators of αSyn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of αSyn toxicity.
    Keywords:  20S proteasome; Parkinson disease; alpha‐synuclein; autophagy; posttranslational modifications; proteasomal chaperones; protein homeostasis; yeast
    DOI:  https://doi.org/10.1111/acel.70566
  4. Protein Sci. 2026 Jun;35(6): e70635
    Biophysical assessment of the molecular mechanisms of Tau aggregation and its role in Alzheimer's disease.
    Joshua T Skrehot, Dmitry Kurouski.
      Alzheimer's disease (AD) is characterized by the intracellular aggregation of the microtubule-associated protein Tau. While the presence of large, insoluble neurofibrillary tangles has long been the primary focus of this research, a paradigm shift in the field now highlights smaller, soluble oligomers as the more neurotoxic Tau species leading to neuronal death and cognitive decline. This leaves the important and ill-understood question of what molecular events lead to the conversion of healthy, functional Tau into these toxic oligomers. This review addresses the knowledge gap by investigating existing literature on the upstream mechanisms responsible for the onset of neurodegeneration and connecting it to disease pathogenesis. By synthesizing evidence from molecular biophysics, cellular biology, and neuropathology, this review summarizes the most recent understanding of factors contributing to pathological Tau aggregation, including post-translational modifications, lipids, and metal ions, among others. This review also discusses how neurotoxic Tau aggregates contribute to the onset of AD. By connecting these factors with findings from mammalian brain studies, this review establishes a comprehensive timeline of pathology that demystifies the transition from physiological Tau to toxic oligomers and links specific molecular triggers to the onset of neurodegeneration.
    Keywords:  Alzheimer's disease; Tau; fibrils; oligomers; post translational modifications
    DOI:  https://doi.org/10.1002/pro.70635
  5. J Biol Chem. 2026 May 23. pii: S0021-9258(26)02056-9. [Epub ahead of print] 113184
    p53 regulates mitochondrial function and alpha-synuclein aggregation in Parkinson's disease.
    Kaiying Hou, Jialin Chen, Yuxin Xie, Tingting Liu, Jiaying Li, Chong Meng, Dongxue Niu, Meiyan Xian, Jingwen Li, Chaoyang Zhu, Hong Li, Jianshe Wei.
      Parkinson's disease (PD) is the second most common neurodegenerative disease, in which mitochondrial dysfunction and abnormal aggregation of alpha-synuclein (α-syn) play key roles in the pathology of PD. As a classic tumor suppressor, p53 has also been found to be involved in the pathological process of PD in recent years. However, the specific mechanism by which p53 regulates mitochondrial function and abnormal aggregation of α-syn is still unclear. Here, we observed that the expression of α-syn and p53 was increased and mitochondria were impaired in the MPTP-induced PD mouse model, leading us to propose speculation on whether p53 affects mitochondrial impairment and abnormal α-syn aggregation in PD pathology. Next, cellular experiments revealed that the p53 inhibition by pifithrin-α regulates mitochondrial function through mitophagy and mitochondrial dynamics, then ameliorates oxidative stress and apoptosis in PD. Meanwhile, the in vitro study showed that the p53 protein interacted with α-syn to accelerate the process of α-syn liquid-liquid phase separation and amyloid fibril formation, promoting the development of PD pathology. In summary, p53 modulates mitochondrial function through mitophagy and mitochondrial dynamics, stimulating the pathogenic aggregation of α-syn protein and neurodegeneration in Parkinson's disease.
    Keywords:  Parkinson's disease; alpha-synuclein; mitochondrial dynamics; mitophagy; p53
    DOI:  https://doi.org/10.1016/j.jbc.2026.113184
  6. JACS Au. 2026 May 25. 6(5): 3014-3026
    Local Organization of Biological Membranes Modulates Tau-Lipid Interactions and Fibril formation.
    Clara Piersson, Victoria Lublin, Mathieu Duttine, Lucie Khemtemourian, Antoine Loquet, Marion Mathelié-Guinlet, Yann Fichou.
      The formation of Tau amyloids is a hallmark of several neurodegenerative diseases, called Tauopathies, including Alzheimer's disease. In different Tauopathies, Tau amyloid filaments adopt a distinct structure, highlighting the existence of disease specific pathways. In this pathological context, lipid metabolism is heavily disrupted, leading to a perturbation of membrane composition. Lipid membranes have been shown to nucleate tau aggregation under some conditions. However, no general model has been established to explain how the organization of the lipid membrane modulates Tau aggregation. Here, we combined biochemistry and biophysical tools, including EPR spectroscopy, to investigate the mechanisms of membrane-induced Tau aggregation. After showing the importance of the electrostatic interaction between Tau and anionic lipids, we investigate how the amount and density of charges influence Tau aggregation. This work allows us to draw a general model where membrane-induced Tau aggregation is a two-step process. First, the binding to the membrane through electrostatic interactions is a necessary but not a sufficient step. Second, the nucleation of Tau amyloids at the membrane surface occurs only when specific conditions are fulfilled, i.e., high surface density altering Tau conformation and spatial proximity between aggregation-prone conformers. A direct implication of this model is that local membrane heterogeneities, such as phase separation or lipid rafting, are strong modulators of Tau aggregation. This work provides the molecular basis to predict how different membrane states regulate Tau aggregation.
    Keywords:  EPR spectroscopy; Tau protein; aggregation mechanism; amyloid; lipid membrane
    DOI:  https://doi.org/10.1021/jacsau.6c00374
  7. Biomolecules. 2026 May 16. pii: 733. [Epub ahead of print]16(5):
    Epigenetic Evidence Implies Disturbed Proteostasis and Potentially Protein Aggregation in Suicidality.
    Julija Šmon, Maja Juković, Matea Kršanac, Bobana Samardžija, Alja Videtič Paska, Eva Žerovnik, Katarina Kouter, Nicholas J Bradshaw.
      Suicide is a major public health concern and cause of death worldwide. While progress has been made in understanding molecular pathways involved in suicide, much more work is needed to identify clinically useful biomarkers of suicidality. Disturbed cellular proteostasis and aggregation of specific misfolded proteins are established pathological factors of neurodegenerative diseases. Increasing evidence also suggests that such aggregates often occur in patients with chronic mental illnesses. Recently, genes related to disturbed proteostasis showed differential methylation in individuals who died by suicide compared to controls. These include five genes encoding proteins that aggregate in neurodegenerative and/or mental illness: CRMP1 (also called DPYSL1), DISC1, MAPT (encoding the Tau protein), PRKN (also called PARK2, encoding Parkin), and SOD1. Given the possibility that altered methylation in these genes could affect expression of the proteins they encode, we aimed to review evidence for whether disturbed proteostasis may be a point of overlap between suicidality, neurodegenerative disease, and/or mental illnesses. Epigenetic changes in most of these genes also occur in other neurological disorders. Autophagy, and, to a lesser extent, the ubiquitin-proteasome system, are emerging as potentially impaired in individuals with suicidal tendencies and individuals who died by suicide. Based on this accumulated data, we hypothesise that disturbed proteostasis is likely to be a pathological component of suicidality. It is also plausible that this may lead to the accumulation of aggregated proteins in a similar manner to, and potentially overlapping with, those seen in major mental illnesses. If true, this would have consequences for potential identification of biomarkers for suicidality and should be a priority for future research in the field.
    Keywords:  epigenetics; protein aggregation; proteostasis; suicide
    DOI:  https://doi.org/10.3390/biom16050733
  8. Adv Sci (Weinh). 2026 May 25. e16846
    Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.
    Jia-Qi Liu, Hao Liu, Yu-Xuan Sun, Yuying Li, Xiangyi Liu, Li-Qiang Wang, Zhaofei Yang, Qi Fu, Xiaojiao Xu, Jie Chen, Yingshuang Zhang, Jun Zhou, Weidong Le, Mengchao Cui, Yi Liang.
      Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.
    Keywords:  TDP‐43; amyotrophic lateral sclerosis; mitochondrial impairment; protein aggregation; protein disulfide isomerase; protein phase separation
    DOI:  https://doi.org/10.1002/advs.202516846
  9. J Phys Chem B. 2026 May 28.
    Early α-Synuclein Heterodimerization Kinetics Predict Parkinson's Disease Onset.
    Sachin Chaudhary, Vaishnavi Tammara, Bhargavi Choudhary, Atanu Das.
      Identifying physicochemical predictors that connect protein aggregation to clinical phenotypes remains challenging. Here, we examine whether simulated aggregation descriptors of the intrinsically disordered protein α-synuclein (αS) relate to the clinical age of onset in Parkinson's disease. Using a multiscale simulation framework, we combine coarse-grained (CG) models to quantify the kinetics of early dimerization with atomistic simulations to estimate dimer interaction energies, as well as CG thermodynamic protofilament binding free energies complemented by atomistic calculations. These analyses were performed for wild-type αS and five familial mutants, considering both homo- and heterodimeric species. The time scale of WT-mutant heterodimer formation emerges as a statistically informative predictor of age of onset, whereas homodimer formation kinetics and heterodimer protofilament binding affinities fail miserably. In contrast, homodimer protofilament binding free energies display only moderate correlation, suggesting that late-stage fibril stability alone does not determine disease initiation. Overall, the results are consistent with a two-stage aggregation process in which early oligomeric dynamics may contribute to clinically relevant aggregation behavior.
    DOI:  https://doi.org/10.1021/acs.jpcb.6c00859
  10. Int J Mol Sci. 2026 May 11. pii: 4266. [Epub ahead of print]27(10):
    Protein Modifications and Quality Control System: Target for Alzheimer's Disease Therapy.
    Abdullah Md Sheikh, Shozo Yano, Shatera Tabassum, Jubo Bhuiya, Atsushi Nagai.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The Aβ hypothesis proposes that Aβ accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce Aβ have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both Aβ and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of Aβ-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of Aβ and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on Aβ reduction.
    Keywords:  Alzheimer’s disease; amyloid β peptide; neurodegeneration; neuroinflammations; posttranslational modification; protein quality control system; tau
    DOI:  https://doi.org/10.3390/ijms27104266
  11. J Neuroinflammation. 2026 May 26.
    Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
    Yihan Liu, Shijie Shi, Jingyuan Zhang, Mengyao Huang, Mengxue Wang, Tingting Zhang, Wei Wang, Jie Xiang.
      Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhance microglial α-syn clearance, resulting in reduced α-syn burden and improved PD-CI. Mechanistically, irisin activates integrin αV/β5-FAK axis to promotes microglial phagocytic uptake of α-syn, while concurrently stabilizing HMGB1 to facilitate autophagy-lysosome mediated degradation of internalized α-syn, thereby coupling phagocytic uptake to efficient degradation. In summary, these results highlight a dual-module irisin-integrin αV/β5 mechanism that couples microglial phagocytosis and autophagy-lysosome clearance to reduce α-syn burden and ameliorate PD-CI.
    Keywords:  Clearance; Integrin αV/β5; Irisin; Phagocytosis; α-synuclein
    DOI:  https://doi.org/10.1186/s12974-026-03882-4
  12. Brain Sci. 2026 Apr 30. pii: 485. [Epub ahead of print]16(5):
    Lysophospholipids in Synucleinopathies: A Conceptual Framework Linking Proteostasis and Neuroinflammatory Signaling.
    Tamotsu Tsukahara, Hisao Haniu, Yoshikazu Matsuda.
      Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by progressive α-synuclein (α-Syn) aggregation accompanied by chronic neuroinflammatory changes. However, the mechanistic relationship between disrupted proteostasis and inflammatory signaling remains incompletely defined and may vary across disease stages and clinical subtypes. Lysophospholipids (LPLs) are bioactive lipids derived from membrane phospholipids that participate in diverse cellular processes. These functions are primarily mediated through G protein-coupled receptor (GPCR) signaling, but may also involve direct effects on membrane organization and biophysical properties. In addition to receptor-mediated pathways, the surrounding lipid environment may influence protein behavior, although its role in neurodegenerative processes remains to be fully elucidated. Within this framework, LPLs can be considered not only as signaling molecules but also as modulators of the cellular environment in which proteostasis and inflammatory responses occur. In this review, we adopt a lipid-centered perspective in which LPLs occupy an interface between lipid signaling, protein aggregation, and neuroinflammation. Rather than acting as a single initiating factor, altered lipid metabolism is likely to contribute through multiple interconnected pathways. Although current evidence is largely derived from preclinical studies, it supports a role for lipid-related mechanisms, particularly in early stages of synucleinopathy.
    Keywords:  gut–brain axis; lysophospholipids; microglia; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; proteostasis; synucleinopathies; α-synuclein
    DOI:  https://doi.org/10.3390/brainsci16050485
  13. J Clin Biochem Nutr. 2026 May 01. 78(3): 259-267
    Homocysteine increases phosphorylation and aggregation of α-synuclein.
    Soichi Enomoto, Tadanori Hamano, Rei Asano, Hirohito Sasaki, Tomohisa Yamaguchi, Yuki Kitazaki, Yoshinori Endo, Norimichi Shirafuji, Shu-Hui Yen, Yasuhisa Sawai, Hiroyuki Nakano, Hidenori Onishi, Masamichi Ikawa, Osamu Yamamura, Koji Aoki, Masashi Okuro, Yasunari Nakamoto, Yasuhiro Nishiyama.
      The hyperphosphorylation of α-synuclein (α-Syn) at serine 129 is associated with in its aggregation, culminating in the formation of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs. Plasma homocysteine (Hcy) levels are typically high in PD, particularly in those treated with Levodopa. Therefore, we aimed to investigate the effects of Hcy on phosphorylation and aggregation of α-Syn. The human neuroblastoma cell line 3D5 expressing wild-type α-Syn under the control of a tetracycline-off system was treated with Hcy, and aggregation and phosphorylation of α-Syn were examined. Hcy was cytotoxic to 3D5 cells, and Hcy induced cell shrinkage at a concentration >100 ‍μM. Treatment with Hcy upregulated the levels of α-Syn, increased its phosphorylation at serine 129, and increased casein kinase 2A. Moreover, Hcy treatment significantly increased the level of aggregated form of α-Syn, including oligomers in 3D5 cells. However, folate significantly reversed the Hcy-mediated increase in the levels of total α-Syn and its phosphorylation. In conclusion, Hcy enhances the total α-Syn level, and phosphorylated and oligomeric α-Syn formation, thereby promoting LBs formation.
    Keywords:  homocysteine; oligomerization; phosphorylation; α-synuclein
    DOI:  https://doi.org/10.3164/jcbn.25-119
  14. Biochimie. 2026 May 22. pii: S0300-9084(26)00115-X. [Epub ahead of print]247 12-18
    Mapping Hofmeister cation and anion effects on seeded and unseeded aggregation of TDP-43 and amyloid-β in micelle-assisted seed amplification.
    Naoki Yamahara, Yusuke Nakanishi, Akuto Tahara, Masatoshi Inden, Takayoshi Shimohata, Ryo Honda.
      Seed-amplification assays (SAA) amplify trace protein aggregates and are being developed for early diagnosis of neurodegenerative diseases. We previously demonstrated that the addition of Brij-58 micelles markedly increases the sensitivity of TDP-43 and Aβ SAA by 100-1000-fold, and established micelle-assisted SAA (mSAA). Here we map Hofmeister cation and anion effects on the aggregation of TDP-43(267-414) and Aβ(M1-42) in mSAA using 15 salts. For TDP-43, kosmotropic anions promoted aggregation whereas chaotropic anions inhibited it; cation trends were weaker and substrate-dependent. By contrast, all salts accelerated Aβ aggregation, with Mg2+ and Ca2+ producing the largest effects. In most cases, seeded and unseeded kinetics shifted in parallel; notably, low guanidinium chloride (110-220 mM) preferentially suppressed seed-independent TDP-43 aggregation, thereby improving seed discrimination. These ion-specific behaviors can be interpreted within a protein-decorated micelle working model in which Aβ aggregation is governed primarily by electrostatic screening, whereas TDP-43 aggregation reflects specific-ion-mediated dehydration of micelles and protein surfaces.
    DOI:  https://doi.org/10.1016/j.biochi.2026.05.006
  15. Cell. 2026 May 26. pii: S0092-8674(26)00517-9. [Epub ahead of print]
    TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
    Shuyi Zeng, Shenqing Zhang, Shengnan Zhang, Yun Fan, Wencheng Xia, Feiyang Chen, Chengan Huang, Shiran Lv, Jinxia Lu, Yunpeng Sun, Kaien Liu, Yunxia Li, Yaoyang Zhang, Jian Wang, Cong Liu, Dan Li.
      Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.
    Keywords:  CSF biomarker; MSA; SAA; TPPP/p25; cerebrospinal fluid biomarker; cryo-EM amyloid fibril structure; multiple system atrophy; seed amplification assay; tubulin polymerization promoting protein
    DOI:  https://doi.org/10.1016/j.cell.2026.04.050
  16. Org Biomol Chem. 2026 May 26.
    A β-hairpin mimic built on a fluorinated isoxazoline-β2,2-amino acid as a modulator of Tau protein aggregation.
    Murat Saraç, Julia Kaffy, Kaliroi Peqini, Caterina Vanoni, Alina Wetjen, Lisha Singh, Roland Brandt, Valérie Campanacci, Benoît Gigant, François Giraud, Benoît Crousse, Sandrine Ongeri, Maria Luisa Gelmi, Thierry Milcent.
      Alzheimer's disease (AD), the leading cause of dementia, is a tauopathy characterized by the intraneuronal accumulation of misfolded Tau into neurofibrillary tangles that drive synaptic dysfunction and neuronal loss. Molecular chaperones such as Hsp90 regulate Tau folding, degradation, and aggregation, but full-length chaperones are not viable drugs, prompting the development of peptidomimetics that reproduce protective Hsp90-Tau contacts. We previously reported two β-hairpin peptidomimetics derived from Hsp90, based on a piperidine-pyrrolidine (β-HM1) or on an isoxazoline amino acid (β-HM2) incorporating key hot-spot sequences, that inhibit the aggregation of wild-type and ΔK280 Tau and restore Tau-microtubule interactions in cells. Here, we describe the design and characterization of fluorinated β-HM2 analogues (β-FH1 and β-FH2) as molecular tools to investigate the mechanism of Tau misfolding. β-FH1 and β-FH2 contain a fluorinated isoxazoline-β2,2-amino acid scaffold whose S or R stereochemistry biases the peptidomimetic toward either a fully extended β-strand-like conformation or a β-hairpin fold, respectively. The replacement of the phenyl group of the Isox-β2,2-AA core by a trifluoromethyl substituent was intended to refine Tau anti-aggregation activity, enhance metabolic stability toward proteolysis, and introduce a sensitive 19F NMR probe to monitor Tau-peptidomimetic interactions at the molecular level. The fluorinated analogues completely lost their ability to prevent Tau aggregation in model neurons but caused increased dynamics of the Tau-microtubule interaction. This suggests that subtle changes in β-hairpin preorganization and flexibility impair optimal Tau recognition and affect Tau function in neuronal cell processes. These findings underline the need for finely tuned hairpin architectures in the design of chaperone-mimetic peptides.
    DOI:  https://doi.org/10.1039/d6ob00187d
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