bims-proned 2026-07-19 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–07–19
eleven papers selected by
Verena Kohler, Umeå University

Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.
Unraveling Luteolin's Modulatory Effects on α-Synuclein Aggregation: A Combined Biophysical, Computational, and C. elegans Approach.
Alpha-synuclein-decorated nanoconjugates targeting alpha-synuclein assembly.
Liquid-liquid phase separation of tau in Alzheimer's disease.
Clearance and secretion of α-synuclein by RTN3L-mediated endoplasmic reticulum autophagy.
Tau physiology and pathology: impacts on cellular structures and neurodegenerative diseases.
α-Synuclein Seeds Amplification Assays for Parkinson's Disease and Related Synucleinopathies.
Dopamine Abundance Uncouples Neurodegeneration and Lifespan in a C. elegans Model of Parkinson's Disease.
Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
Combating ageing beyond the cell: Emerging roles of extracellular proteostasis.
Thermodynamic Frontiers in Hemoglobin-Inspired Polymer Science for Diagnosis and Modulation of Neurodegenerative Diseases.

Int J Mol Sci. 2026 Jun 25. pii: 5730. [Epub ahead of print]27(13):

Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.

Youngwon Kim, Yong-Keun Jung.

  Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.

Keywords:  neurodegenerative diseases; proteasome; protein aggregation; proteostasis

DOI:  https://doi.org/10.3390/ijms27135730
Cell Biochem Biophys. 2026 Jul 13.

Unraveling Luteolin's Modulatory Effects on α-Synuclein Aggregation: A Combined Biophysical, Computational, and C. elegans Approach.

Syed Moasfar Ali, Md Nadir Hassan, Nida Zaidi, Muhammad Uzair Ashraf, Mahmood Akbar, Aamir Nazir, Rizwan Hasan Khan.

  Parkinson's disease is associated with amyloid fibrillation of alpha-synuclein (α-syn) that involves the aggregation of protein into insoluble fibrils. In this study, we investigate the effect of luteolin (LUT) on α-syn aggregation in vitro, in silico, and in Caenorhabditis elegans. The decrements in light scattering and ThT fluorescence reveal that there is less formation of α-syn aggregates with an increase in the concentration of LUT. Also, a decrease in the ANS fluorescence depicts less exposure of hydrophobic patches in α-syn in the presence of LUT. Far UV CD data shows that LUT resists conversion structure into beta sheets. Dynamic light scattering and transmission electron microscopy revealed that LUT decreases the size and number of fibrils formed. Additionally, LUT reduced RBC hemolysis, indicating its potential therapeutic value in preventing the formation of toxic aggregates. In vivo studies in C. elegans also show that LUT improves the mitochondrial health, reduces reactive oxygen species (ROS), and enhances worm motility. Computational studies provide probable mechanistic insight that LUT interacted with α-syn via hydrophobic and hydrogen interactions, thus limiting the formation of fibrils by masking the sites that might be involved in aggregation. Consequently, LUT is an inhibitor of α-syn aggregation and may be a potential therapeutic agent against Parkinson's disease.

Keywords:   C.elegans ; Alpha-synuclein; Amyloid; Luteolin; Reactive oxygen species; ThT fluorescence

DOI:  https://doi.org/10.1007/s12013-026-02109-w
Int J Biol Macromol. 2026 Jul 13. pii: S0141-8130(26)03450-1. [Epub ahead of print]375 153505

Alpha-synuclein-decorated nanoconjugates targeting alpha-synuclein assembly.

Marco Carrello, Filippo Busatta, Francisco Ramos-Martín, Andrea Sperotto, Daniele Trivellato, Giulia Leo, Giovanna Viola, Daniele Gori, Mariapina D'Onofrio, Stefano Capaldi, Nicola D'Amelio, Michael Assfalg.

  Alpha-synuclein (αS) is a neuronal protein implicated in synaptic regulation, whose pathological aggregation is a hallmark of synucleinopathies, including Parkinson's disease. Despite its physiological importance, its intrinsically disordered nature and conformational plasticity complicate both mechanistic understanding and therapeutic targeting. Here, we investigate the use of protein-functionalized nanoparticles (NPs) as tools to modulate and probe αS assembly pathways, including aggregation and liquid-liquid phase separation. We designed three nanoconjugates by covalently attaching single-cysteine αS variants at positions 18, 76, and 140, spanning the protein's three functional regions, onto PEG-coated silica NPs. These conjugates preserved the disordered character of αS, exhibited low cytotoxicity, and were internalized into neuronal cells. Functional assays revealed site-dependent effects on aggregation: NP-αSA76C significantly delayed αS fibril formation and further inhibited aggregation of the amyloidogenic tau protein, suggesting interference with nucleation mechanisms, while NP-αSA18C modestly accelerated aggregation and showed strong affinity for mature fibrils. All nanoconjugates partitioned into αS condensates, though without marked site-specific differences, and interacted with model lipid membranes. Overall, αS-functionalized NPs influence protein aggregation and condensate interactions, with context-dependent site specificity. These findings highlight the importance of conjugation position in tuning NP-protein interactions and underscore the potential of these nanoconjugates for investigating and modulating pathological protein assembly in neurodegenerative diseases.

Keywords:  Alpha-synuclein; Nanoconjugate; protein aggregation

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153505
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00009-7. [Epub ahead of print]187 219-279

Liquid-liquid phase separation of tau in Alzheimer's disease.

Sangita Rajkhowa, Timir Tripathi.

  Tau is a microtubule-associated protein that plays a central role in neuronal stability and axonal transport. However, under pathological conditions, it undergoes structural and functional changes that lead to Alzheimer's disease (AD) and related tauopathies. Recent evidence highlights liquid-liquid phase separation (LLPS) as a critical mechanism underlying tau aggregation and the subsequent formation of neurofibrillary tangles (NFTs). This chapter explores the properties of tau, including its intrinsically disordered nature, isoforms, and post-translational modifications (PTMs), that predispose it to LLPS. We discuss the thermodynamic and molecular principles of LLPS, with emphasis on the interplay between multivalent interactions, crowding effects, RNA binding, and cofactors that modulate the formation of tau condensates. Special attention is given to the transition from dynamic, reversible tau droplets to irreversible fibrillar assemblies. The chapter further examines how truncation and PTM cross-talk alter the phase behavior and aggregation propensity of tau. Cellular implications of tau LLPS, including its role in stress granules, synaptic dysfunction, and seeding of NFTs, are also analyzed. Finally, we highlight the regulatory roles of chaperones, metal ions, and interacting proteins and underscore the therapeutic potential of targeting tau phase separation. Together, this synthesis positions the LLPS of tau as a pivotal event in AD pathogenesis and a promising target for therapeutic intervention.

Keywords:  Alzheimer’s disease; Intrinsically disordered proteins (IDPs); Liquid–liquid phase separation (LLPS); Neurofibrillary tangles; Post-translational modifications (PTMs); Protein aggregation; RNA–protein interactions; Stress granules; Tau protein

DOI:  https://doi.org/10.1016/bs.irn.2026.01.009
Mol Biol Cell. 2026 Jul 15. mbcE26030138

Clearance and secretion of α-synuclein by RTN3L-mediated endoplasmic reticulum autophagy.

Yihong Ye, Kamal Kumar, Yue Xu, Fenfen Xu, Susan Ferro-Novick.

The misfolding and aggregation of α-synuclein (α-syn), an abundant synaptic protein, leads to the pathogenesis of Parkinson's disease and related synucleinopathies. The cell-to-cell propagation of seeding-competent α-syn is initiated by unconventional protein secretion, yet the physiological pathway(s) underlying this process remain poorly defined. Here we show that α-syn secretion in human cells is mediated by Reticulon-3L (RTN3L)-dependent endoplasmic reticulum autophagy (ER-phagy), a conserved protein quality-control pathway that safeguards ER protein homeostasis. We also demonstrate that RTN3L cooperates with several autophagy regulators, including the ULK1 cofactor FIP200, to drive the delivery of α-syn into an acidic endolysosomal compartment. Increasing concentrations of α-syn disrupt ER-lysosome traffic and α-syn-containing vesicles appear to be rerouted to the cell surface. Consistent with this proposal, knockdown of vesicle associated SNAREs, that mediate fusion at the cell surface, disrupt α-syn secretion. These findings suggest that pathogenic α-syn secretion arises as a by-product of a physiological clearance mechanism, driven by the fusion of autophagosome-derived vesicles with the plasma membrane. Our results provide a conceptual framework for understanding how an intracellular proteostasis pathway, when mis-regulated, could contribute to the spread of neurodegenerative pathology.

DOI: https://doi.org/10.1091/mbc.E26-03-0138
Inflammopharmacology. 2026 Jul 14.

Tau physiology and pathology: impacts on cellular structures and neurodegenerative diseases.

Vali Akbari, Seifollah Bahramikia.

  This review explores the crucial roles of the tau protein in neuronal integrity and its dysregulation in neurodegenerative diseases (NDs), particularly tauopathies. Key features include abnormal tau phosphorylation, leading to insoluble aggregates and neuronal dysfunction. Various therapeutic strategies, such as reducing tau phosphorylation, inhibiting aggregation, and enhancing clearance through autophagy and immunotherapies, are discussed. Promising candidates such as anle138b and methylene blue display efficacy in preclinical models. The interplay between tau and Aβ pathology is also highlighted, emphasizing the complexity of therapeutic approaches. A thorough understanding of tau functions is essential for developing targeted treatments to combat tau-related neurotoxicity and advance therapies for Alzheimer's disease (AD). This article examines the dual role of tau in physiology and pathology, highlighting its effects at both the cellular and subcellular levels. These findings underscore the critical importance of the tau protein in preventing NDs and suggest that a deeper understanding of its functions could improve treatment strategies for tau-related disorders.

Keywords:  Aggregation; Alzheimer's disease; Neurodegenerative diseases; Tauopathies

DOI:  https://doi.org/10.1007/s10787-026-02328-w
Med Res Rev. 2026 Jul 16.

α-Synuclein Seeds Amplification Assays for Parkinson's Disease and Related Synucleinopathies.

Rosalie Elvira, Qing Wang, Yu-Cheng Wu, Eng King Tan, Zhi Dong Zhou.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the pathological misfolding and aggregation of α-synuclein (α-syn), which leads to dopaminergic neuronal loss and multisystem dysfunction. Conventional clinical diagnosis is often delayed until after substantial neuronal degeneration has occurred. Recent advances in α-syn seed amplification assays (α-syn SAAs), including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have revolutionized PD biomarker research. These assays exploit the prion-like seeding and propagation properties of pathological α-syn to amplify trace aggregates in biological samples with exceptional sensitivity and specificity. Here, we summarize the mechanistic principles and biophysical underpinnings of α-syn SAAs, compare their diagnostic performance across biospecimens such as cerebrospinal fluid, skin, blood, and saliva, and evaluate their potential for differential diagnosis among synucleinopathies. We further discuss the integration of SAAs with other biomarkers including α-syn oligomer ELISAs, neurofilament light chain assays, and dopaminergic PET/SPECT imaging. Emerging developments, such as same-day RT-QuIC, quantitative kinetic readouts, and peripheral blood-based assays, are accelerating clinical translation. Despite challenges in assay standardization, strain discrimination, and regulatory validation, α-syn SAAs hold transformative potential for early diagnosis, patient stratification, and monitoring of therapeutic efficacy in PD. Their convergence with artificial intelligence, organoid modeling, and multimodal biomarker frameworks promises to redefine precision medicine in PD and other synucleinopathies.

Keywords:  Parkinson's disease; early diagnosis; neurodegenerative biomarkers; precision medicine; seed amplification assay; synucleinopathies; α‐synuclein

DOI:  https://doi.org/10.1002/med.70080
bioRxiv. 2026 Jul 09. pii: 2026.07.04.736516. [Epub ahead of print]

Dopamine Abundance Uncouples Neurodegeneration and Lifespan in a C. elegans Model of Parkinson's Disease.

Corey W Willicott, Tyler J Altman, Logan C Kimble, Laura A Berkowitz, Guy A Caldwell, Kim A Caldwell.

The neuropathology of Parkinson's disease is characterized by α-synuclein (α-syn) aggregation and dopaminergic (DAergic) neurodegeneration. While neuronal loss in C. elegans α-syn-induced neurodegeneration models is temporally age-dependent, prior research indicates it is uncoupled from the organismal aging process. Here we examined transgenic C. elegans expressing human A53T α-syn in DAergic neurons to determine the impact of localized DA metabolism on both neurodegeneration and organismal lifespan. Increasing endogenous DA levels through overexpression of tyrosine hydroxylase (CAT-2) exacerbated A53T-induced DAergic degeneration, whereas DA depletion via Δ cat-2 mutation rescued neuronal survival. By mutating a DA-interaction motif within α-syn, neurodegeneration was rendered insensitive to DA manipulation, thus confirming a structural basis for in vivo toxicity. We identified a DA-α-syn interaction that acts as a common upstream bridge whereby localized stress induces physiological responses in C. elegans . Genetically, this biochemical interaction acts as a pleiotropic trigger driving two compartmentalized responses: localized DAergic neurodegeneration via oxidative stress, and organism-wide, TFEB/ hlh-30 -dependent proteostatic remodeling that extends lifespan. Modulating autophagy, without exacerbating DA-mediated oxidative stress, represents a promising strategy to preserve adaptive systemic remodeling while limiting targeted neuronal damage.

DOI: https://doi.org/10.64898/2026.07.04.736516
Mol Neurobiol. 2026 Jul 17. pii: 775. [Epub ahead of print]63(1):

Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.

Shobha Kumari, Hemraj Singh, Shravani Vaidya, Rajeev Taliyan.

  Neurodegenerative diseases are characterized by progressive neuronal loss driven by protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Among these, Parkinson's disease (PD) is a prevalent disorder marked by degeneration of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates. Emerging evidence indicates that mitochondrial dysfunction and metabolic dysregulation are central contributors to PD pathogenesis. Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, have emerged as key regulators of neuronal survival and metabolic homeostasis. Mechanistically, SIRT1 regulates α-synuclein aggregation, autophagy, and neuroinflammatory signaling, while SIRT3 preserves mitochondrial integrity and reduces oxidative stress. In contrast, SIRT2 has been implicated in microtubule destabilization and neurotoxicity, and its inhibition has demonstrated neuroprotective effects in experimental models. This review provides a comprehensive, up-to-date synthesis of the molecular mechanisms underlying sirtuin-mediated neuroprotection in PD and related neurodegenerative disorders. We further discuss the translational potential of targeting sirtuin pathways, including pharmacological modulators and NAD+-boosting strategies, while addressing current limitations and future directions for clinical translation.

Keywords:  Epigenetic regulation; Mitochondrial dysfunction; NAD+ metabolism; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Sirtuins

DOI:  https://doi.org/10.1007/s12035-026-06062-w
FEBS J. 2026 Jul 12.

Combating ageing beyond the cell: Emerging roles of extracellular proteostasis.

Siddharth R Venkatesh, Ivan Gallotta, Bolanle F Olabiyi, Yoon Hee Choi, Sarah Inglesfield, Janet R Kumita, Collin Y Ewald, Della C David.

  Proteostasis, the maintenance of a healthy proteome, is a fundamental pillar of cellular and organismal health that declines with age. While the intracellular proteostasis network (PN) is well-characterised, proteostasis mechanisms acting in the extracellular space remain understudied. Yet, these mechanisms face unique challenges and are critical for ensuring functional systemic signalling, immune surveillance and structural integrity. In contrast to the cytosol, extracellular environments lack ATP-activated chaperones and a comprehensive ubiquitin-proteasome system and instead rely on specialised secreted chaperones, extracellular proteases and receptor-mediated clearance mechanisms. This review examines the emerging landscape of the extracellular proteostasis network (exPN) and its challenges with age. We discuss how age-related remodelling of the extracellular proteome, shifts in extracellular physicochemical properties and disrupted fluid dynamics collectively create a permissive environment for protein misfolding and aggregation. We evaluate current experimental models of extracellular protein damage and examine how exPN factors target specific stages of the aggregation process to cooperatively safeguard extracellular proteome integrity. Analysis of recent human proteomic data spanning the life course uncovers an unexpected upregulation of exPN components with age. We further explore the role of extracellular proteostasis in inflammageing, a defining hallmark of ageing. Finally, we highlight strategies that bolster extracellular proteostasis as a promising frontier for extending healthspan, limiting age-associated protein aggregation and restoring extracellular matrix homeostasis. By adopting an ageing-centred perspective, we move beyond the disease context to present a holistic overview of extracellular proteostasis in organismal health, thereby positioning the exPN as a critical yet under-exploited target for biomedical intervention.

Keywords:  ageing; extracellular chaperones; extracellular matrix; extracellular proteases; extracellular proteostasis network; immunity; protein aggregation

DOI:  https://doi.org/10.1111/febs.70647
Cell Biochem Funct. 2026 Jul;44(7): e70261

Thermodynamic Frontiers in Hemoglobin-Inspired Polymer Science for Diagnosis and Modulation of Neurodegenerative Diseases.

Mohammad Edrisi, Navid Rabiee.

  The thermodynamic logic underlying hemoglobin's cooperative binding and reversible conformational transitions offers a powerful conceptual model for reimagining polymer design in neurodegenerative medicine. In this review perspective, we outline a unified thermodynamic framework that connects molecular energetics, polymer science, and pathological protein aggregation. We discuss how hemoglobin's allosteric adaptability, enthalpy-entropy compensation, and redox responsiveness can inspire polymers capable of sensing and reshaping the free-energy landscapes that govern amyloid formation. Drawing on evidence from protein thermodynamics, polymer chemistry, and neurobiological systems, we propose design principles for adaptive, hemoglobin-inspired polymers that act as artificial chaperones, materials capable of modulating aggregation equilibria, restoring proteostatic balance, and integrating diagnostic and therapeutic functions. This article defines an emerging field at the intersection of thermodynamic polymer science and neurodegeneration, where materials are not passive carriers but active regulators of molecular energy landscapes.

Keywords:  Artificial chaperone materials; Energy landscape re‐engineering; Hemoglobin‐inspired polymers; Protein aggregation and neurodegeneration; Thermodynamic medicine

DOI:  https://doi.org/10.1002/cbf.70261