bims-proned 2026-05-17 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–05–17
eleven papers selected by
Verena Kohler, Umeå University

Distinct Molecular Mechanisms Underlie Modulation of Seeded α-Synuclein Aggregation and Toxicity by Salvianolic Acid B and Dihydromyricetin.
Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.
Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.
A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.
Mechanism of Aggregation of the NACore of α-Synuclein: Stable Oligomer Formation Competes with Fibril Formation with Implications for the Etiology of Parkinson's Disease.
Psychiatric and behavioral disorders in Parkinson's disease: co-pathogenic mechanisms of tau, Aβ, and α-synuclein proteins (narrative review).
NMR characterization of the structure and interaction of an RNA aptamer targeting α-synuclein.
α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
Detecting the seeds of Parkinson's disease: the evolution of α‑synuclein seed amplification assay as a clinical biomarker.
Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.

Int J Mol Sci. 2026 Apr 26. pii: 3843. [Epub ahead of print]27(9):

Distinct Molecular Mechanisms Underlie Modulation of Seeded α-Synuclein Aggregation and Toxicity by Salvianolic Acid B and Dihydromyricetin.

Nishant N Vaikath, Iman W Achkar, Indulekha P Sudhakaran, Ilham Y Abdi, Janarthanan Ponraj, Omar M A El-Agnaf.

  Aggregation and seeded propagation of α-synuclein (α-syn) are central to the pathogenesis of Parkinson's disease and related synucleionopathies. Modulation of seeded aggregation and amplification of pathological α-syn species represents a promising strategy for limiting disease progression. Here, we investigated the effects of naturally derived polyphenolic compounds on α-syn fibrillation, seeded aggregation, and associated cytotoxicity. Among the compounds examined, salvianolic acid B and dihydromyricetin exhibited significant inhibitory effects on α-syn aggregation. Biochemical and biophysical analyses using Thioflavin-T fluorescence, Congo Red binding, and transmission electron microscopy demonstrated that both compounds inhibited fibril formation and altered fibril morphology. Notably, dihydromyricetin efficiently disaggregated preformed fibrils and suppressed seeded fibril elongation, whereas salvianolic acid B primarily delayed aggregation kinetics. Both compounds significantly reduced α-syn-induced cytotoxicity in BE(2)-M17 cells. These findings demonstrate that salvianolic acid B and dihydromyricetin differentially modulate key steps in the α-syn aggregation pathway and reduce associated cellular toxicity. Collectively, these results provide mechanistic insight into the modulation of seeded α-syn aggregation and identify salvianolic acid B and dihydromyricetin as effective modulators of pathological α-syn assembly.

Keywords:  Parkinson’s disease; aggregation; polyphenolic inhibitors; α-synuclein

DOI:  https://doi.org/10.3390/ijms27093843
Protein Pept Lett. 2026 ;33(1): 258-274

Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.

Vidhan Chand Bala, Mukesh Kumar Singh, Amit Kumar, Sunil Kumar Tiwari, Asheesh Kumar Gupta, Rakesh Chawla, Sushil Kumar.

  Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; neurodegeneration; synucleinopathies; α- synuclein

DOI:  https://doi.org/10.2174/0109298665429866260217115717
Commun Biol. 2026 May 12.

Early α-synuclein-mediated mitochondrial dysfunction in a human cell model of Parkinson's disease dementia.

Maha S Alfaidi, Léa M D Wenger, Kornélia Szebényi, Thomas B Stoker, Xiaoling He, Shaline V Fazal, Jana Sebestikova, Amir Jassim, Richard J Gilbertson, Raquel Garza, Johan Jakobsson, Maria Grazia Spillantini, Roger A Barker, Wei-Li Kuan.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and accumulation of α-synuclein (α-syn) into pathological aggregates known as Lewy bodies. PD remains incurable, partly due to limited physiologically relevant models that recapitulate human pathology to enable therapeutic development. We developed a novel in vitro PD dementia model using fetal human cortical neurons seeded with α-syn preformed fibrils (PFFs). This model successfully replicates key PD features, including α-syn aggregation and mitochondrial gene dysregulation. Importantly, RNA sequencing revealed significant transcriptomic concordance between our model and PD postmortem tissue, particularly in the downregulation of mitochondrial genes linked to oxidative phosphorylation. We then evaluated two peptide inhibitors, β-syn36D (B36D) and S62. Both peptides demonstrated effective disaggregation of α-syn fibrils, with B36D showing particular promise by reversing PFF-induced functional and transcriptional changes to baseline levels. This human-relevant model captures essential pathological and transcriptomic disease hallmarks as well as demonstrating utility for therapeutic screening of drugs that block α-syn aggregation.

DOI: https://doi.org/10.1038/s42003-026-10134-x
bioRxiv. 2026 Feb 24. pii: 2026.02.23.706428. [Epub ahead of print]

A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.

Gillian E Gadbois, Alexander P Plonski, Galia T Debolouchina, Fleur M Ferguson.

Pathological seeding of protein misfolding is a hallmark of proteinopathies. However therapeutic strategies to clear these aggregates are lacking, impairing both study of their biological importance in disease etiology and progression as well as development of therapeutics. This is due in part to the need to selectively clear oligomerized proteins whilst leaving functional monomers intact, as well as the challenge of developing molecules that act on the full complement of 'misfolds' the protein can adopt throughout the course of disease. In this work, we describe a dopant system consisting of an engineered alpha-synuclein protein construct that rapidly co-aggregates into existing WT alpha-synuclein oligomers, enabling rapid degradation of the entire assembly in the presence of a small molecule trigger. This work provides proof-of-principle for an approach that transforms pathological seeding from a disease-driver into a therapeutic vulnerability, and is potentially applicable to any proteinopathy without requiring a small molecule binder of the pathologic species.

DOI: https://doi.org/10.64898/2026.02.23.706428
J Am Chem Soc. 2026 May 12.

Mechanism of Aggregation of the NACore of α-Synuclein: Stable Oligomer Formation Competes with Fibril Formation with Implications for the Etiology of Parkinson's Disease.

Yingying Jin, Pritam Ganguly, Lena Wessel, Zhiyuan Zhu, Anouk M Rijs, Joan-Emma Shea, Steven K Buratto, Michael T Bowers.

NACore peptides, derived from the hydrophobic core region of α-synuclein, serve as a critical model for understanding amyloid fibril formation, a hallmark of neurodegenerative diseases such as Parkinson's. This study integrates atomic force microscopy (AFM), ion mobility-mass spectrometry (IM-MS), and molecular dynamics (MD) simulations to investigate the structural dynamics of NACore aggregation under varying conditions of time, concentration, and pH. The results reveal distinct concentration-dependent aggregation pathways, where stable early-stage oligomers such as tetramers and hexamers form at low concentrations while fibril formation predominates at higher concentrations. A subtle change in environmental pH significantly modulates these pathways: neutral pH (7.4) facilitates the formation of diverse and relatively stable oligomeric species, including hexamers and octamers, while basic pH (8.0) stabilizes tetramers as off-pathway intermediates that may delay fibril formation. Conversely, at acidic pH (6.8), oligomerization is limited, with the system predominantly remaining monomeric and small, with unstable oligomers likely acting as fibril precursors. AFM and IM-MS characterize oligomer size and stability, while MD simulations highlight the molecular stability of cylindrin-like tetramers and hexamers. These findings emphasize the complexity of NACore aggregation and provide valuable insights into oligomer formation pathways, thereby providing opportunities to design potential therapeutic strategies targeting specific intermediates to modulate amyloid formation.

DOI: https://doi.org/10.1021/jacs.6c01293
Rev Neurosci. 2026 May 14.

Psychiatric and behavioral disorders in Parkinson's disease: co-pathogenic mechanisms of tau, Aβ, and α-synuclein proteins (narrative review).

Ju-Yuan Chai, Yong Zhang, Zhen-Qiang Zhang, Dong-Rui Ma, Yi-Han Cao, Shi-Rui Zhu, Yun-Zhi Ma, Lin-Lin Luo, Ya-Li Zhan, Zi-Yan Fan, Rui Lan.

  Parkinson's disease (PD) is a common neurodegenerative disorder affecting middle-aged and elderly individuals. Its clinical manifestations include both motor and non-motor symptoms. Traditionally, Lewy bodies (LBs), which are formed by misfolded α-synuclein (α-syn), have been regarded as the core pathological hallmark. It is believed that the selective damage to dopaminergic neurons in the nigrostriatal system by LBs constitutes the primary mechanism underlying motor symptoms. However, approximately 30-80 % of PD patients also experience psychiatric and behavioral disturbances, such as anxiety, depression, cognitive impairment, and sleep disorders. The pathological mechanisms underlying these symptoms cannot be fully explained by α-syn alone. Recent biomarker studies have confirmed that hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs) and amyloid β-protein (Aβ) plaques can coexist with α-syn in the brains of PD patients, especially in advanced stages. These coexisting pathologies show significant positive correlations with cognitive impairment and sleep disorders, suggesting that the neuropsychiatric symptoms in PD may result from the synergistic effects of multiple protein pathologies involving α-syn, tau, and Aβ. This review synthesizes these findings to propose an integrated "synergistic co-pathogenic network" of α-syn, tau, and Aβ, thereby providing a novel theoretical framework for developing precise, multi-target therapeutic strategies against PD-related neuropsychiatric disorders.

Keywords:  Parkinson’s disease; amyloid β-protein; psychiatric disorders; tau protein; α-synuclein

DOI:  https://doi.org/10.1515/revneuro-2026-0041
Biochem Biophys Res Commun. 2026 Jul 09. pii: S0006-291X(26)00638-8. [Epub ahead of print]821 153874

NMR characterization of the structure and interaction of an RNA aptamer targeting α-synuclein.

Xiang Li, Yudai Yamaoki, Takashi Nagata, Kazuma Murakami, Masato Katahira.

  α-Synuclein (αSyn) is an intrinsically disordered protein whose aberrant aggregation is a hallmark of Parkinson's disease. C-terminally truncated αSyn variants promote aggregation and fibril formation of full-length αSyn, making them targets for diagnosis and therapy. sh1R6 is an RNA aptamer selected against a C-terminally truncated αSyn variant (αSyn1-95). sh1R6 binds αSyn1-95 with high affinity and suppresses fibril formation of full-length αSyn, but its recognition mechanism remains unclear. In this study, NMR spectroscopy was used to determine the structure of sh1R6 and its mode of interaction with αSyn. The imino-imino NOEs indicated that sh1R6 adopts a stem-loop (hairpin) structure. Upon addition of αSyn1-95, TOCSY spectra of sh1R6 showed pronounced attenuation of H5-H6 correlations of pyrimidine residues in the loop region, thereby identifying the loop and adjacent residues as the primary binding interface. In parallel, addition of sh1R6 to full-length αSyn caused chemical shift perturbations (CSPs) in both the N-terminal and C-terminal regions. These CSPs suggest binding of sh1R6 to the N-terminal region, including the P1 region, a key determinant of αSyn fibril formation, and possible disruption of long-range intramolecular interactions between the N-terminal and C-terminal regions. Thus, in place of the C-terminus, sh1R6 may bind the N-terminal region with higher affinity and mask the N-terminal region including P1 region, thereby preventing αSyn aggregation and fibril formation. Together, these findings define the binding interface between sh1R6 and αSyn1-95 and provide structural and mechanistic insights into how 1R6 modulates αSyn aggregation.

Keywords:  NMR spectroscopy; Parkinson's disease; RNA aptamer; α-Synuclein (αSyn)

DOI:  https://doi.org/10.1016/j.bbrc.2026.153874
Nat Commun. 2026 May 15.

α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.

Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.

Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-κB-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-Syn-induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.

DOI: https://doi.org/10.1038/s41467-026-73136-7
J Neural Transm (Vienna). 2026 May 14.

Detecting the seeds of Parkinson's disease: the evolution of α‑synuclein seed amplification assay as a clinical biomarker.

Juan Miguel Bautista, Christyn Jezza Quanico, Paulo Cataniag, Jose Gil Guillermo, Nobutaka Hattori.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein (α-syn) aggregation, but diagnosis is still largely clinical and often delayed. α-syn seed amplification assays (α-syn SAAs), including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have enabled sensitive detection of misfolded α-syn, offering a promising biomarker for early and objective diagnosis. This narrative review evaluates the development and diagnostic performance of α-syn SAA across different biological specimens in PD and related synucleinopathies. Literature from 2016 to 2026 was reviewed across major databases, focusing on studies addressing assay methodology, diagnostic accuracy, and clinical application, with narrative synthesis. α-syn SAAs demonstrate consistently high diagnostic accuracy, with pooled sensitivity ranging from approximately 0.86-0.88 and specificity from 0.92 to 0.96. Cerebrospinal fluid remains the most validated specimen; however, peripheral tissues such as skin, blood, and olfactory or gastrointestinal samples show increasing diagnostic utility with comparable specificity in several studies. Large cohorts confirm strong performance in both symptomatic and prodromal PD. Kinetic and strain differences also support disease stratification and differentiation among synucleinopathies. α-syn SAA represents a major advancement in the biomarker landscape of PD, enabling direct detection of misfolded protein pathology across multiple biospecimens with high diagnostic accuracy. Key limitations include lack of standardization, but ongoing advances support its clinical translation and integration into molecular classification frameworks.

Keywords:  Alpha-synuclein; Parkinson's disease; Parkinson's disease biomarker; Protein misfolding cyclic amplification (PMCA); Real-time quaking-induced conversion (RT-QuIC); Seed amplification assay

DOI:  https://doi.org/10.1007/s00702-026-03174-4
BMC Med. 2026 May 14.

Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Yoshitaka Tamaki, Shunya Kaneko, Makoto Urushitani.

   BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio.
SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.

Keywords:  Molecular Zipper hypothesis; NTD; RRM; TDP-43; dimerization

DOI:  https://doi.org/10.1186/s12916-026-04935-4
Narra J. 2026 Apr;6(1): e3042

Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.

Meutia A Faradilla, Karina S Anastasya, Deasyka Yastani, Yohana Yohana, Endrico X Tungka, Suweino Suweino.

  Aging is the primary risk factor for major neurodegenerative disorders, yet the precise molecular links between biological aging and progressive neuronal loss remain complex. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, has emerged as a central converging mechanism driving both processes. This review aims to synthesize current evidence demonstrating how chronic redox imbalance drives cellular senescence and neuronal vulnerability through mitochondrial dysfunction, lipid peroxidation, and oxidative protein damage. These insights underscore how sustained oxidative insults promote the misfolding and aggregation of disease-defining proteins, including amyloid-beta in Alzheimer's disease and α-synuclein in Parkinson's disease, thereby amplifying neuroinflammation, synaptic dysfunction, and bioenergetic failure. Furthermore, antioxidant-based therapeutic strategies are critically reassessed, highlighting a paradigm shift from non-specific radical scavenging toward targeted modulation of endogenous defense systems, particularly NRF2 signaling and mitochondria-directed antioxidants. By integrating molecular mechanisms with translational perspectives, this review integrates molecular, cellular, and translational evidence to explain how oxidative stress links biological aging to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

Keywords:  Oxidative stress; aging; mitochondria; neurodegeneration; reactive oxygen species

DOI:  https://doi.org/10.52225/narra.v6i1.3042