bims-proned 2025-08-31 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–08–31
eighteen papers selected by
Verena Kohler, Umeå University

Converging pathologies in neurodegeneration: the mechanistic interplay between α-Synuclein and Tau in Alzheimer's and Parkinson's.
IR Action Spectroscopy of Mass- and Mobility-Selected α-Synuclein Segments: Structure Identification in Early-Stage Oligomers via the Amide A Region.
Uncovering the protein aggregation process through effect of G41D mutant SOD1 charge variation in ALS disease.
Intrinsically Disordered to Stable and Reversible α-Helical Conformational Transition of α-Synuclein in a Neat Polymer Surfactant Mesophase.
Direct Observation of Amyloid-β 42 Oligomer, Fibril, and Amorphous Aggregate Growth and Dissolution at Biomimetic Concentrations.
Tauopathies: Calmodulin Regulates Tau Hyperphosphorylation and Its Transformation into Disease-Specific Aggregates.
GDNF attenuates a-synuclein aggregation-induced damage to VTA-NAc dopaminergic transmission and alleviates depression-like behaviors in mice.
Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia.
Seed Amplification Assay for α-Synuclein: Diagnostic Applications in Synucleinopathies.
Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer's Disease.
Two-dimensional materials can inhibit Aβ fibrillation in Alzheimer's disease.
Nfe2l1 dysfunction alters Parkinson's disease-related gene expression and impairs neuronal differentiation under ubiquitin stress in neuronal differentiated P19 Cells.
Astrocyte alterations in α-synucleinopathies.
Conformational Ensemble Dynamics of Intrinsically Disordered Full-Length α- and β-Synuclein Monomers.
The role of mitophagy in perioperative neurocognitive disorder: from mechanisms to implications.
Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.
Neuronal expression of S100B triggered by oligomeric Aβ peptide contributes to protection against cytoskeletal damage and synaptic loss.
The Role of the human microbiome in neurodegenerative diseases: A Perspective.

Neurol Sci. 2025 Aug 26.

Converging pathologies in neurodegeneration: the mechanistic interplay between α-Synuclein and Tau in Alzheimer's and Parkinson's.

Jeyaram Bharathi Jeyabalan, Vignesh Pandi A, Sankar Veintramuthu, Ramasamy Sivasamy, Muralikrishnan Dhanasekaran, Antony Justin.

  Alzheimer's and Parkinson's disease are the most prevalent neurodegenerative disorders globally, each characterized by distinct pathological hallmarks; primarily tau neurofibrillary tangles and amyloid-beta plaques in AD, and alpha-synuclein (α-Syn) Lewy bodies in PD. However, evidence suggests a complex interplay between these proteins, particularly α-Syn and tau, which may contribute to the progression of both diseases. Recent observations demonstrate the co-occurrence of α-Syn and tau pathologies in both AD and PD patients. At the molecular level, both proteins exhibit prion-like propagation properties and can undergo cross-seeding, where one misfolded protein species induces the misfolding, aggregation of the other and increasing neurotoxicity. These proteins also share common post-translational modifications, cellular clearance mechanisms, and are influenced by similar microenvironmental factors that favor protein aggregation. This review explores the potential mechanisms by which α-Syn in PD may influence tau pathology, potentially exacerbating AD like disease progression that may potentially contribute to cognitive decline in PD. This review also delves into the underlying molecular pathways, such as prion-like propagation, cross-seeding, and inflammatory responses that could mediate this interaction, leading to enhanced neurodegeneration in comorbid cases. Further, various clinical implications of proteins' interplay, relevance to mixed neurodegenerative phenotypes, and potential therapeutic strategies targeting both α-Syn and tau pathologies have also been discussed in this manuscript.

Keywords:  Alzheimer’s; Cross-seeding; Neurodegeneration; Parkinson’s disease; Prion-like propagation

DOI:  https://doi.org/10.1007/s10072-025-08421-2
J Phys Chem A. 2025 Aug 21.

IR Action Spectroscopy of Mass- and Mobility-Selected α-Synuclein Segments: Structure Identification in Early-Stage Oligomers via the Amide A Region.

Agathe Depraz Depland, Olivier Verhoev, Steven Daly, Anouk M Rijs.

Parkinson's disease (PD) is associated with protein misfolding and aggregation of α-Synuclein (α-Syn), a process central to its pathology. Understanding the early structural transitions of α-Syn is crucial, yet detailed insights into oligomeric intermediates remain elusive. Using the novel Photo-Synapt spectrometer, which integrates ion mobility mass spectrometry (IM-MS) with infrared multiple-photon dissociation (IRMPD) spectroscopy, we investigated the secondary structures of key α-Syn peptide segments, namely, WT-PD1 (NACore) and WT-PD2 (pre-NAC). This unique approach enabled conformationally selective analysis, allowing peptide monomers and oligomers to be separated based on both mass and mobility. Despite sequence similarities, these peptides exhibit distinct monomeric structures and aggregation behavior, leading to different oligomer assemblies with unique IR signatures. By analyzing the amide A region (3100-3500 cm-1), we provide structural insight into α-Syn oligomer structure, including the resolution of parallel versus antiparallel β-sheets and the identification of non-β motifs such as γ-turns. We further examined the G51D mutation from the pre-NAC region (G51D-PD2), which induces a more compact structure and stabilizes oligomers, leading to distinct IR spectral features. Combining IM-MS and IRMPD spectroscopy within a single instrument provides a novel structural readout for early-stage peptide aggregation. This approach highlights the high sensitivity of sequence-dependent structural transitions in α-Synuclein oligomers, providing insight into the mechanistic pathways of sequence-dependent folding relevant to disease.

DOI: https://doi.org/10.1021/acs.jpca.5c02819
Sci Rep. 2025 Aug 27. 15(1): 31661

Uncovering the protein aggregation process through effect of G41D mutant SOD1 charge variation in ALS disease.

Zainab Abdullah Waheed, Abasalt Hosseinzadeh Colagar, Bagher Seyedalipour, Payam Baziyar.

  Neurodegenerative disorders are a group of hereditary and sporadic conditions that are characterized by progressive nervous system dysfunctions. Mutations in the gene encoding human superoxide dismutase 1 (hSOD1) were among the first to be proposed in line with the protein aggregation theory for ALS disease. This study aimed to characterize the (G41D) mutation/charge effects on the biochemical and biophysical properties of the SOD1 structure through computational and experimental methods. The computed average values of RMSD, RMSF, and Rg demonstrate that mutation results in a loss of conformational stability, increased flexibility, and greater compactness, all supporting the observed aggregation. The G41D mutant revealed distinct changes in β-sheet content compared to WT-SOD1 under amyloidogenic conditions, as confirmed by FTIR spectroscopy. Furthermore, the formation of amyloid/amorphous species was identified using ThT/ANS fluorescence and confirmed by TEM analysis. Mutations that alter the net negative charge of the SOD1 protein are crucial in misfolding and shortening the lag phase in SOD1 aggregation. Our results provide supporting evidence that these charge alterations, alongside amyloid-inducing agents at near-physiological pH, significantly contribute to the formation of amyloid-like species. Therefore, studying the G41D mutation may provide valuable insights into the mechanisms of fALS-associated aggregate formation, which holds promise for the development of highly effective inhibitors in reducing aggregates and therapeutic potential.

Keywords:  Molecular dynamics (MD) simulations; Protein aggregation; SOD1; fALS; β-strands (β4)

DOI:  https://doi.org/10.1038/s41598-025-16910-9
Biomacromolecules. 2025 Aug 22.

Intrinsically Disordered to Stable and Reversible α-Helical Conformational Transition of α-Synuclein in a Neat Polymer Surfactant Mesophase.

Anwesha Maity, Rajlaxmi Panigrahi, Amit Chaudhary, Ajay S Panwar, Ashutosh Kumar, Kamendra P Sharma.

α-synuclein (α-Syn), an intrinsically disordered protein associated with Parkinson's disease, exhibits a high propensity for aggregation under physiological and in vitro conditions, even at low concentrations. This necessitates its storage in the lyophilized form at ≤ -20 °C. In this work, we demonstrate that dispersing native α-Syn in an aqueous solution of poly(ethylene glycol)(PEG)-based polymer surfactant (PS), followed by lyophilization, forms a viscoelastic material at room temperature, in which α-Syn adopts a highly stable and reversible α-helical secondary structure. Solid-state NMR analysis reveals that helix formation involves alanine, threonine, and valine residues, predominantly within the N-terminal and NAC regions. Interestingly, small-angle X-ray scattering (SAXS) studies indicate that a neat PS matrix exhibits a distorted lamellar mesophase; however, it becomes ordered upon α-Syn incorporation. All-atom MD simulations show that PS hydrophobic domains self-assemble into "nematic-like" structures that selectively interact with the hydrophobic residues in α-Syn. These findings establish polymer-driven strategies for long-term storage and structure-function stabilization of various therapeutic proteins.

DOI: https://doi.org/10.1021/acs.biomac.5c00583
J Phys Chem B. 2025 Aug 27.

Direct Observation of Amyloid-β 42 Oligomer, Fibril, and Amorphous Aggregate Growth and Dissolution at Biomimetic Concentrations.

Radhika Sunil Menon, Peter G Wolynes, Peter G Vekilov.

The aggregation pathways of Aβ42 peptides are complex and can lead to both amyloids and nonamyloid aggregates. We use in situ atomic force microscopy imaging to monitor the assembly of aggregate structures and their dynamics. Two aggregation pathways emerge, one leading to amyloid fibrils and a second one that includes the formation of oligomers and apparently amorphous aggregates, which we identify as nonamyloid. Whereas the fibrils seem to require elevated peptide concentration to nucleate and grow, oligomers and amorphous aggregates form at near-physiological peptide concentrations. On the time scales of the experiments, the two aggregation pathways do not cross: the oligomers and aggregates do not participate in the fibrillization pathway and, analogously, secondary nucleation assisted by mature fibrils does not produce misfolded aggregates. We show that distinct Aβ42 fibril polymorphs form and coexist under identical conditions. Mature fibrils serve as substrates for secondary nucleation that leads to forked, branched, and thicker fibrils and, importantly, produces new fibril fragments. Aβ42 fibrils accumulate structural defects, with more defects generated at higher peptide concentrations. The defects lead to substantial variations of growth rate both over time and between different fibrils. The average growth rates of Aβ42 fibrils are about 50-fold faster than those of Aβ40 fibrils. Our findings are consistent with the basic premise of the polymorph selection hypothesis, according to which the late onset of Alzheimer's disease, its high clinical variability, and the presence of amyloid plaques in healthy individuals have their origins in differing toxicities and aggregation kinetics of distinct Aβ structural polymorphs.

DOI: https://doi.org/10.1021/acs.jpcb.5c03842
Biomolecules. 2025 Aug 06. pii: 1133. [Epub ahead of print]15(8):

Tauopathies: Calmodulin Regulates Tau Hyperphosphorylation and Its Transformation into Disease-Specific Aggregates.

Danton H O'Day.

  Tauopathies are a diverse group of neurodegenerative diseases characterized by the presence of Tau inclusions in neurons and glia. Rather than the classic steps in the transformation of Tau into neurofibrillary tangles, as first studied in Alzheimer's disease, studies on tauopathies reveal the presence of diverse Tau aggregates that appear to be disease-specific. Regardless, the phosphorylation and hyperphosphorylation of Tau, involving various kinases and phosphatases, appear to be central to all tauopathies. As in other neurodegenerative diseases, calcium dysregulation is an early event in multiple tauopathies, where it activates calmodulin to effect downstream events. Here, the events of Tau phosphorylation and hyperphosphorylation, which involve several CaM-dependent kinases and a single CaM-regulated phosphatase, are covered. In addition, CaM has been linked to other events, including Tau aggregation. As a central player in tauopathies, CaM offers several alternative therapeutic routes that are worth investigating. For example, evidence is presented here that supports targeting specific binding motifs of key CaM-regulated Tau kinases as a novel therapeutic approach.

Keywords:  CaMKII; Calmodulin Hypothesis; Cdk5; GSK3B; MARK4; Tau phosphorylation; calcineurin; calmodulin binding domains; calpain; therapeutic approaches

DOI:  https://doi.org/10.3390/biom15081133
Sci Rep. 2025 Aug 21. 15(1): 30804

GDNF attenuates a-synuclein aggregation-induced damage to VTA-NAc dopaminergic transmission and alleviates depression-like behaviors in mice.

Jing Chen, Zhi Ling, Maokang Lv, Shengzhe Chen, Wei Xu, Lin Shao, Zifan Ma, Chuanxu Wang, Yuanjian Song, Chuanxi Tang.

  Dopamine (DA) transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is strongly associated with depression in Parkinson's disease (PD). Decreased DA levels due to alpha-synuclein (α-syn) aggregation have been underappreciated in relation to depression in PD. This study investigated the role of VTA-related α-syn aggregation in depression of PD, and whether gial cell line-derived neurotrophic factor (GDNF) can inhibit α-syn aggregation to improve symptoms. Here, α-syn aggregation and GDNF overexpression were induced in the VTA of 8-week-old male mice (C57BL/6J, DAT-cre, D2-cre) using adeno-associated viruses, combined with a cis-tracer virus as well as a chemogenetic virus. Behavioral tests, immunofluorescence (IF), western blot (WB), and enzyme-linked immunosorbent assay (ELISA) were employed for analysis. The mice with increased p-α-syn in VTA exhibited depressive-like behavior, along with reduced DA levels in the VTA and NAc, as well as reduced expression of related proteins in the NAc. However, GDNF overexpression in the VTA, led to a decrease in p-α-syn expression and reversed the aforementioned phenomena. Furthermore, results from cis-tracer virus and Immunofluorescence (IF) assay revealed a reduction in transmission of DA from the VTA to the NAc in mice with α-syn aggregation, which can be reversed by GDNF overexpression. Additionally, chemogenetic virus-induced diminished D2-MSN activation in the NAc significantly ameliorated depression-like behavior due to α-syn aggregation in the VTA. In conclusion, the aggregation of α-syn within the VTA may contribute to depression in PD, while GDNF can alleviate depression by inhibiting α-syn aggregation.

Keywords:  Alpha-synuclein; Depression; Dopamine D2-type receptors; Glial cell line-derived neurotrophic factor; Parkinson’s disease

DOI:  https://doi.org/10.1038/s41598-025-16556-7
Protein Sci. 2025 Sep;34(9): e70240

Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia.

Alladi Charanraj Goud, Ihor Kozlov, Patricie Skoupilová, Lukáš Malina, Sudeep Roy, Viswanath Das.

  Tau aggregation driven by microtubule-associated protein tau (MAPT) mutations is central to frontotemporal dementia pathology, yet no disease-modifying therapies effectively target mutant tau. Here, we identify purpurin (PUR) and oleocanthal (OLC) as selective inhibitors of mutant tau aggregation using peptide models spanning the R2R3 interface. Biophysical and cellular assays demonstrated that both compounds more effectively inhibit the aggregation of mutant tau peptides compared to wild-type, with PUR preferentially targeting V287I and N279K variants, and OLC showing broader inhibitory activity. Surface plasmon resonance and docking analyses revealed more stable interactions and lower binding free energies with mutant tau, consistent with their enhanced inhibitory effects. Computational studies using monomeric and fibrillar tau structures supported the mutation-specific binding profiles of PUR and OLC. Atomic force microscopy and confocal imaging confirmed reduced fibril formation, while post-transduction treatment assays showed that both compounds significantly suppressed intracellular tau propagation. Additionally, OLC reduced tau phosphorylation and oligomerization in SY5Y-TauP301L-EGFP cells expressing mutant tau. These findings highlight the potential of PUR and OLC as structurally distinct, mutation-targeted inhibitors of tau aggregation and propagation, providing a rationale for their further development as candidate therapeutics for frontotemporal dementia.

Keywords:  MAPT mutations; frontotemporal dementia; oleocanthal; purpurin; seeding competency; surface plasmon resonance; tau aggregation; tauopathies

DOI:  https://doi.org/10.1002/pro.70240
Int J Mol Sci. 2025 Aug 13. pii: 7817. [Epub ahead of print]26(16):

Seed Amplification Assay for α-Synuclein: Diagnostic Applications in Synucleinopathies.

Alexandros Giannakis, Louisa Pechlivani, Chrissa Sioka, George Alexiou, Spiridon Konitsiotis, Athanassios P Kyritsis.

  Seed amplification assays (SAA) targeting misfolded α-synuclein have emerged as powerful tools for the diagnosis and study of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies, and multipßle system atrophy. These assays exploit the prion-like seeding properties of pathological α-synuclein to detect minute amounts of misfolded protein in biological specimens. the PubMed database was searched according to our study criteria, and 55 clinical studies comprised the final literature review. the majority of studies have focused on patients at various stages of PD, with cerebrospinal fluid (CSF) being the most commonly investigated biological specimen. Diagnostic utility was most pronounced in the CSF of PD patients, whereas results from other biological samples and across different synucleinopathies have been more modest. α-syn SAA demonstrate significant diagnostic potential in synucleinopathies. Additional applications may include monitoring disease progression. Future studies should explore the utility of α-syn SAA in alternative biological specimens, assess its performance across various synucleinopathies and other neurodegenerative diseases, and determine its comparative diagnostic value.

Keywords:  Parkinson’s disease; dementia with Lewy bodies; diagnosis; multiple system atrophy; seed amplification assay; α-synuclein

DOI:  https://doi.org/10.3390/ijms26167817
ACS Chem Neurosci. 2025 Aug 27.

Modulation of Amyloid-β Aggregation by Surface Proteins from Pathogens Associated with Alzheimer's Disease.

Antonin Kunka, Hana Hribkova, Tereza Vanova, Veronika Pospisilova, Martin Havlasek, Jan Haviernik, Daniel Ruzek, Jiri Damborsky, Dasa Bohaciakova, Zbynek Prokop.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. Despite substantial research efforts, our understanding of its pathogenesis remains incomplete, limiting the development of effective treatments and preventive strategies. The potential role of microbial pathogens in AD etiology has gained increasing attention. Various human microbial pathogens have been identified in the brains of AD patients, leading to the pathogen hypothesis, which posits that these microorganisms may disrupt the brain's immune regulation and homeostasis. In this study, we examine the effects of proteins from three pathogens, Borrelia burgdorferi, HSV-1, and Porphyromonas gingivalis, on the aggregation of antimicrobial peptide amyloid-β (Aβ). Three of the four studied proteins were found to attenuate the aggregation of Aβ42 by interacting with its soluble form and inhibiting primary and secondary pathways. These in vitro findings were further supported by experiments using mature neurons derived from human pluripotent stem cells, which showed an increased accumulation of amyloid precursor protein (APP) aggregates upon infection with HSV-1 or exposure to the OspA surface protein from B. burgdorferi. Together, our results provide mechanistic insights into how pathogen-associated proteins modulate Aβ42 aggregation, contributing to an understanding of their potential role in AD pathogenesis.

Keywords:  Alzheimer’s disease; amyloid-β; amyloids; neuroinflammation; pathogen; virus

DOI:  https://doi.org/10.1021/acschemneuro.5c00444
Phys Chem Chem Phys. 2025 Aug 26.

Two-dimensional materials can inhibit Aβ fibrillation in Alzheimer's disease.

Anupam Ghosh, Titas Kumar Mukhopadhyay, Ayan Datta.

Alzheimer's disease (AD) is a major life-limiting neurodegenerative disorder caused by extracellular aggregation of amyloid β (Aβ) peptides. This forms amyloid plaques in the brain resulting in dementia and even causing death. In spite of great efforts towards developing therapies to cure AD, unfortunately, treatment is often ineffective. Herein, we investigate the possibility of state-of-the-art two-dimensional (2D) nanomaterials to treat AD by evaluating their potential to perturb and disrupt Aβ peptide aggregates. The adsorption mechanism for a pre-formed Aβ fibril is carefully studied on five 2D materials, namely graphene, hexagonal boron nitride (h-BN), h2D-C2N, g-C3N3, and g-C3N4. They are screened for their disrupting effects on the peptide aggregate. It is found that disruption of the Aβ fibril is directly related to the strength of its adsorption on the 2D material, which in turn, is dominated by the van der Waals interactions. h-BN shows a profound disruption of the Aβ fibril followed by graphene. The nitrogen-containing carbon-based 2D materials, h2D-C2N, g-C3N3, and g-C3N4, are found to be rather poor in this aspect. Structural disruption parameter ρd is proposed as an index to rank the potency of 2D materials to inhibit Aβ fibrillation. h-BN and graphene are shown to be highly potent towards disruption of misfolded protein aggregates like Aβ fibrils.

DOI: https://doi.org/10.1039/d5cp01461a
Sci Rep. 2025 Aug 20. 15(1): 30542

Nfe2l1 dysfunction alters Parkinson's disease-related gene expression and impairs neuronal differentiation under ubiquitin stress in neuronal differentiated P19 Cells.

Hossein Khodadadi, Dawid Winiarczyk, Kamila Łuczyńska, Hiroaki Taniguchi.

  Proteostasis is essential for neuronal health, and its disruption is implicated in neurodegenerative diseases such as Parkinson's disease (PD). Nfe2l1, a key regulator of proteostasis and ubiquitination, plays a significant role in neuronal health, yet its molecular functions in neuronal cells remain unclear. Our study investigates the role of Nfe2l1 in RA-induced neuronal differentiation of P19 cells under proteasome inhibition. This condition significantly increased Nfe2l1 expression at both protein and RNA levels in wild-type and differentiated cells. In differentiated cells under proteasome inhibition, RNA sequencing revealed an enrichment of neurodegenerative pathways, particularly those associated with PD. Proteasome inhibition led to the upregulation of several PD-related genes, including Atf6, Camk2d, and Sod1. However, Nfe2l1 knockdown in differentiated cells significantly reduced the expression of these genes, highlighting the role of Nfe2l1 in the regulation of PD-related pathways. Knockdown of Nfe2l1 also decreased Neat1, a long non-coding RNA associated with PD pathology, and downregulated the neuronal marker Map2, indicating impaired neuronal differentiation. Furthermore, Nfe2l1 knockdown increased ubiquitination under proteasome inhibition, emphasizing its role in protein degradation and neuronal homeostasis under stress. These findings highlight Nfe2l1 as a critical regulator in neuronal cells and reveal its potential role in maintaining proteostasis and involvement in neurodegenerative disease mechanisms, such as PD.

Keywords:  Neurodegeneration; Neurogenesis; Nfe2l1; Parkinson’s disease; Proteotoxic stress; Transcriptomic analysis

DOI:  https://doi.org/10.1038/s41598-025-08204-x
Front Cell Neurosci. 2025 ;19 1650326

Astrocyte alterations in α-synucleinopathies.

Manuela Rodríguez-Castañeda, Ana Campos-Ríos, Jose Antonio Lamas, Ana Covelo.

  Despite long being considered to be passive and supportive cells, in the last decades astrocytes have arisen as key regulators of neuronal excitability, synaptic transmission and plasticity. Since the discovery of the tripartite synapse, accumulating evidence suggests that astrocytes are involved in the pathogenesis of neurodegenerative diseases, including α-synucleinopathies. Here we will discuss recent evidence showing that astrocytes express endogenous α-synuclein and the implications of this protein in astrocyte cellular processes. Furthermore, we review how the expression of pathological forms of this protein in astrocytes leads to aberrant cytosolic Ca2+ activity in these cells and to alterations in gliotransmission and pathology progression.

Keywords:  astrocytes; gliotransmission; tripartite synapse; α-synuclein; α-synucleinopathies

DOI:  https://doi.org/10.3389/fncel.2025.1650326
J Chem Inf Model. 2025 Aug 25.

Conformational Ensemble Dynamics of Intrinsically Disordered Full-Length α- and β-Synuclein Monomers.

Zhongyue Lv, Huan Xu, Ying Zhang, Huayuan Tang, Feng Ding, Fengjuan Huang, Yunxiang Sun.

Abnormal aggregation of α-synuclein (αS) into amyloid fibrils is a hallmark of neurodegenerative diseases such as Parkinson's disease. In contrast, its homologue β-synuclein (βS), colocalized at presynaptic terminals, resists amyloid formation and can even inhibit αS fibrillization. However, how sequence variations affect their structural dynamics remains poorly understood. To address this, we conducted 100 independent 1000 ns atomistic discrete molecular dynamics simulations for both αS and βS monomers. Our results revealed that both proteins predominantly adopted intrinsically disordered conformations, punctuated by transient helices and β-sheets. Both αS and βS exhibited a conserved helical tendency in the first half of the N-terminal domain, while the latter half showed dynamic β-sheet characteristics with αS displaying greater abundance. Notably, the nonamyloid component (NAC) region in αS─critical for its aggregation─frequently adopted dynamic β-sheet structures, whereas the homologous region in βS displayed a greater tendency toward dynamic helices. Despite being largely disordered, the C-terminal regions transiently interacted with β-sheet-prone segments, potentially acting as dynamic caps that limit β-sheet growth in both proteins. Free-energy landscape analysis indicated a clear enthalpy-entropy trade-off: structured conformations were stabilized by lower potential energy but penalized by reduced entropy, whereas disordered states, despite higher potential energy, were entropically favored. Importantly, potential energy reduction in αS was primarily associated with β-sheet formation, while in βS, it was mainly driven by helix formation. These findings offer mechanistic insights into the distinct conformational landscapes of αS and βS and establish a thermodynamic framework for understanding how sequence differences modulate their structural properties and functional roles.

DOI: https://doi.org/10.1021/acs.jcim.5c01602
Neuroscience. 2025 Aug 18. pii: S0306-4522(25)00868-1. [Epub ahead of print]584 160-165

The role of mitophagy in perioperative neurocognitive disorder: from mechanisms to implications.

Shuai Gao, Jiaqiang Wang, Jiawei Chen.

  Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperativepatients, seriously impacting their postoperative recovery and cognition as well as quality of life. The occurrence of PND is closely related to various factors, including neuroinflammation and oxidative stress, while the exact mechanism is still unknown. Mitophagy is a specialized form of autophagy and maintains cellular homeostasis by selectively degrading damaged and dysfunctional mitochondria, serving as a crucial quality control mechanism to ensure the mitochondrial network's integrity and functionality. Mitophagy has been proved to be involved in the onset and progression of major neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Recently, findings indicated that mitophagy may also play critical roles in the pathogenesis of PND, and the mechanisms may involve ubiquitin-dependent pathways (such as the PINK1/Parkin pathway) and non-ubiquitin-dependent pathways (such as the BNIP3/FUNDC1 pathway). Studies indicated that the PINK1/Parkin pathway is impaired in the animal PND models. In contrast, the BNIP3/ FUNDC1 pathway is neuroprotective by promoting mitophagy under stress conditions such as hypoxia. In addition, abnormal Tau protein aggregation and ferroptosis are correlated with mitophagy and PND in animal studies. In this review, we focused on the role and detailed mechanism of mitophagy in the occurrence and development of PND, as well as on possible potential targets involving mitophagy modulation.

Keywords:  Cognitive function; Ferroptosis; Mitophagy; Perioperative neurocognitive disorder (PND); Signal pathway; Tau protein

DOI:  https://doi.org/10.1016/j.neuroscience.2025.08.028
Biomedicines. 2025 Aug 20. pii: 2025. [Epub ahead of print]13(8):

Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS.

Victor Voicu, Corneliu Toader, Matei Șerban, Răzvan-Adrian Covache-Busuioc, Alexandru Vlad Ciurea.

  Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization-spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways-including PI3K-AKT-mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades-undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome-lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3-CR3 axis), and excitatory-inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network "meaning-making"-a collapse of coordinated signal interpretation, triage prioritization, and adaptive response-the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning-a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration.

Keywords:  RNA-binding protein dysfunction; TDP-43 proteinopathy; glial–neuronal signaling entropy; mTOR–autophagy axis; neurodegeneration dynamics; precision neurotherapeutic strategies; proteostasis network collapse; signal transduction failure; stress granule pathology; synaptic integrity breakdown

DOI:  https://doi.org/10.3390/biomedicines13082025
Front Mol Neurosci. 2025 ;18 1636365

Neuronal expression of S100B triggered by oligomeric Aβ peptide contributes to protection against cytoskeletal damage and synaptic loss.

Joana Saavedra, Mariana Nascimento, António J Figueira, Marina I Oliveira da Silva, Tiago Gião, João Oliveira, Márcia A Liz, Cláudio M Gomes, Isabel Cardoso.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular deposition of amyloid-β peptide (Aβ). AD is also characterized by neuroinflammation and synapse loss, among others. The S100 family is a group of calcium-binding proteins with intra- and extracellular functions, that are important modulators of inflammatory responses. S100B, which is upregulated in AD patients and the most abundant member of this family, was shown to inhibit in vitro the aggregation and toxicity of Aβ42, acting as a neuroprotective holdase-type chaperone. Although S100B is primarily produced by astrocytes, it is also expressed by various cells, including neurons. In this work, we investigated if S100B neuronal expression is triggered as a response to Aβ toxic species, to provide protection during disease progression. We used the AD mouse model AβPPswe/PS1A246E to show that neuronal S100B levels are significantly higher in 10-month-old animals, and cellular assays to demonstrate that Aβ oligomers significantly increase S100B expression in SH-SY5Y cells, but not monomeric or fibrillar Aβ. Using primary cultures of rat hippocampal neurons, we showed that S100B partially reverts Aβ-induced cofilin-actin rods (synapse disruptors), and rescues the decrease in active synapses and post-synaptic marker (PSD-95), imposed by Aβ peptide. Altogether, these findings establish the neuroprotective activity of S100B in response to proteotoxic stress in cells, highlighting its chaperone function as a crucial factor in understanding proteostasis regulation in the diseased brain and identifying potential therapeutic targets.

Keywords:  Alzheimer’s disease; Aβ oligomers; S100B; cytoskeleton dysfunction; molecular chaperones; neuroprotection; synapse loss

DOI:  https://doi.org/10.3389/fnmol.2025.1636365
Curr Genet. 2025 Aug 21. 71(1): 17

The Role of the human microbiome in neurodegenerative diseases: A Perspective.

Nilabha Mukherjea, Ashwin Khandelwal, Rohit Saluja, Neetu Kalra.

  Advances in diagnostics, therapeutics, and large-scale clinical studies have significantly expanded our understanding how human health is shaped by the microorganisms that colonize the body since birth. This article explores the rapidly evolving field of human microbiome research, focusing upon how microbial communities influence neurological health and contribute to the development of neurodegenerative diseases (NDs). Multiple factors, including age, lifestyle, and immunological memory, are recognized as major determinants of an individual's microbiome composition, which in turn can influence the onset and the progression of disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions have been linked to mechanisms including the aggregation of pathogenic proteins (e.g., amyloid-β and α-synuclein), inflammation driven by activation of the Toll-like receptor (TLR) signaling pathway, the NLRP3 inflammasome, as well as the modulatory effect of microbial metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS). The article also highlights ongoing research and emerging strategies aimed at leveraging the human microbiome for better diagnosis, and management of NDs.

Keywords:  Alzheimer's disease dysbiosis ; Microbiome; Neurotransmitters; Parkinson’s disease

DOI:  https://doi.org/10.1007/s00294-025-01319-8