bims-proned 2026-02-22 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–02–22
thirteen papers selected by
Verena Kohler, Umeå University

TMEM106B deficiency exacerbates α-synuclein aggregation in Parkinson's disease.
The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
Effects of Arginine on Hierarchical Protein Aggregation.
A universal phase-plane model for in vivo protein aggregation.
Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation.
Hydration Shell of PEO-PPO-PEO Block Copolymer Assembly Controls the Modulation of Protein Aggregation: Synergistic Inhibition of Fibrillation Using Trehalose and Protection from Cu2+-Induced Fibrillation.
Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.
Revealing the invisible: a new imaging paradigm for α-synuclein pathology in Parkinson's disease.
Diagnostics of Synucleinopathies by Protein Amplification Methods: Methodological and Bibliometric Analysis.
β-Hydroxybutyrate attenuates glycation-induced structural destabilization and amyloidogenic aggregation in human serum albumin.
Structural defects in amyloid-β fibrils drive secondary nucleation.
Nanoscopic tau aggregates are not shared intermediates but disease-specific entities across tauopathies.
Rotating Magnetic Field Therapy Induces System-Level Neuroprotection in A53T α-Synuclein Transgenic Mice Through Coordinated Suppression of Cellular Stress Pathways.

Brain. 2026 Feb 17. pii: awag065. [Epub ahead of print]

TMEM106B deficiency exacerbates α-synuclein aggregation in Parkinson's disease.

Lanxia Meng, Congcong Liu, Meihui Li, Huangchuan Gong, Xiaoling Gu, Wenxuan Zou, Han Liu, Hanying Teng, Jing Xiong, Zhentao Zhang.

  Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation have not yet been fully identified. TMEM106B is a lysosomal transmembrane protein that has been reported to be associated with brain aging and neurodegenerative diseases including Parkinson's disease. Here we show that TMEM106B is reduced in the brains of patients with Parkinson's disease. Knockdown of TMEM106B increases the formation of α-synuclein aggregates in primary neurons and mouse brains. TMEM106B deficiency results in impaired lysosomal acidification, lipid metabolism disorders, and lipid droplet deposition in neurons. Interestingly, lipid droplets promote α-synuclein aggregation, resulting in the formation of α-synuclein fibrils with enhanced seeding activity and neurotoxicity compared with α-synuclein fibrils formed in the absence of lipid droplets. TMEM106B deficiency also leads to retardation of α-synuclein degradation by reducing the enzymatic activity of the lysosomal protease cathepsin D. Taken together, these results indicate that TMEM106B deficiency contributes to Parkinson's disease pathogenesis by accelerating α-synuclein aggregation and halting α-synuclein degradation.

Keywords:  Parkinson’s disease; lipid metabolism; neurodegenerative diseases; transmembrane protein 106B (TMEM106B)

DOI:  https://doi.org/10.1093/brain/awag065
J Biol Chem. 2026 Feb 16. pii: S0021-9258(26)00162-6. [Epub ahead of print] 111292

The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.

Biswarathan Ramani, Kean Ehsani, Martin Kampmann.

  Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 co-chaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 co-chaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPRi screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 co-localized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.

Keywords:  aggregation; chaperone; high-throughput screening; neurodegeneration; polyglutamine disease

DOI:  https://doi.org/10.1016/j.jbc.2026.111292
Protein J. 2026 Feb 20.

Effects of Arginine on Hierarchical Protein Aggregation.

Suguru Nishinami, Yoshiki Kihara, Teruo Akuta, Kentaro Shiraki, Tsutomu Arakawa.

  Arginine is widely used in protein formulations to suppress protein aggregation and prolong the lifetime of the native, functional state which undergoes different stresses during storage, shipping and handling. However, arginine's differential effects on protein aggregation pathways remain unclear. Here, we investigated the effects of arginine on heat- and acid-induced aggregation of immunoglobulin G and heat-induced aggregation of several model proteins. Arginine suppressed the formation of insoluble aggregates but had limited impact on monomer recovery, particularly on immunoglobulin G. Instead, arginine promoted the formation of soluble aggregates, suggesting a possibility that unfolded proteins possess heterogeneous surface properties, leading to formation of soluble and insoluble aggregates that are modulated by arginine. To explain these kinetic behaviors, we propose a hierarchical aggregation model, in which arginine preferentially modulates weaker intermolecular interactions to inhibit the growth of the soluble aggregates into large insoluble aggregates. Moreover, soluble aggregates were observed in a range of proteins with varying isoelectric points and molecular weights. These results highlight a previously unrecognized aspect of soluble protein aggregation. Understanding the pathway and mechanism of soluble aggregate formation may shed light into physiologically-relevant soluble assemblies, e.g., Alzheimer's disease-associated oligomers and microtubule-derived double rings in contrast to the soluble amorphous aggregates under current study.

Keywords:  Additive–protein interaction; Arginine; Protein aggregation; Soluble aggregates

DOI:  https://doi.org/10.1007/s10930-026-10324-w
J Chem Phys. 2026 Feb 21. pii: 075101. [Epub ahead of print]164(7):

A universal phase-plane model for in vivo protein aggregation.

Matthew W Cotton, Alain Goriely, David Klenerman, Georg Meisl.

Neurodegenerative diseases are driven by the accumulation of protein aggregates in the brain of affected individuals. The aggregation behavior in vitro is well understood and driven by the equilibration of a super-saturated protein solution to its aggregated equilibrium state. However, the situation is altered fundamentally in living systems, where active processes consume energy to remove aggregates. It remains unclear how and why cells transition from a state with predominantly monomeric protein, which is stable over decades, to one dominated by aggregates. Here, we develop a simple but universal theoretical framework to describe cellular systems that include both aggregate formation and removal. Using a two-dimensional phase-plane representation, we show that the interplay of aggregate formation and removal generates cell-level bistability, with a bifurcation structure that explains both the emergence of disease and the effects of therapeutic interventions. We explore a wide range of aggregate formation and removal mechanisms and show that phenomena such as seeding arise robustly when a minimal set of requirements on the mechanism are satisfied. By connecting in vitro aggregation mechanisms to changes in cell state, our framework provides a general conceptual link between molecular-level therapeutic interventions and their impact on disease progression.

DOI: https://doi.org/10.1063/5.0312752
Biophys Chem. 2026 Feb 04. pii: S0301-4622(26)00023-2. [Epub ahead of print]332 107590

Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation.

Khaled M Jami, Katherine E Corbett, Daniel C Farb, Kayla M Osumi, Catelynn C Shafer, Sophie Criscione, Dylan T Murray.

  The loss of cellular proteostasis through aberrant stress granule formation is implicated in neurodegenerative diseases. Stress granules are formed by biomolecular condensation involving protein-protein and protein-RNA interactions. These assemblies are protective, but can rigidify, leading to amyloid-like fibril formation, a hallmark of the disease pathology. Key proteins dictating stress granule formation and disassembly, such as TDP43, contain low-complexity (LC) domains that drive fibril formation. HSPB8, a small heat shock protein, localizes to stress granules, has known aggregation delaying activity, and helps direct aggregated proteins to protein degradation pathways. It is not known how HSPB8 interacts with aggregation prone LC domains in stress granules. Here, we examine the interaction between isolated HSPB8 and the TDP43 LC using thioflavin T (ThT) and fluorescence polarization (FP) aggregation assays, fluorescence microscopy and photobleaching experiments, and crosslinking mass spectrometry (XL-MS). Our results indicate that HSPB8 delays TDP43 LC aggregation through domain-specific interactions with fibril nucleating species, without affecting fibril elongation rates. These findings provide mechanistic insight into how HSPB8 mediates LC domain aggregation and provides bases for investigating how the TDP43 LC subverts chaperone activity in neurodegenerative disease and comparing differing mechanisms between members of the HSPB protein family.

Keywords:  ATP-independent chaperone; Biomolecular condensate; Liquid droplet; Protein aggregation; Protein fibril; RNA-binding protein; Small heat shock protein

DOI:  https://doi.org/10.1016/j.bpc.2026.107590
ACS Appl Bio Mater. 2026 Feb 16.

Hydration Shell of PEO-PPO-PEO Block Copolymer Assembly Controls the Modulation of Protein Aggregation: Synergistic Inhibition of Fibrillation Using Trehalose and Protection from Cu2+-Induced Fibrillation.

Nidhi Anilkumar Jamuna, Dharini Arumugam, Sarthak Mandal.

  Amyloid aggregation is a key process involved in many neurodegenerative diseases including Alzheimer's disease. It affects the brain and peripheral tissues, where different types of protein aggregates are accumulated. Pluronic PEO-PPO-PEO block copolymer self-assemblies are widely used as nanocarriers for the brain-targeted delivery of therapeutic agents. Elucidating protein aggregation at these polymer interfaces can provide critical insights into how macromolecular crowding and protein-polymer interactions influence the kinetics of protein aggregation. Here, we investigate the roles of two pluronic copolymers, namely, P123 and F127, which have a similar size of hydrophobic PPO block but different PEO block length on protein aggregation using hen egg white lysozyme (HEWL) as a model protein. Our study reveals that the more hydrated F127 self-assemblies with thicker PEO hydration shells accelerate the onset of protein-aggregation yet moderately retard the extent of overall fibril formation. On the other hand, the less hydrated P123 self-assemblies with compact hydration shells significantly delay the onset of protein aggregation and efficiently inhibit fibril formation. The binding of protein within the hydrated and longer PEO corona of F127 micelles favors accelerated kinetics of β-rich oligomers and fibril formation without a delay phase through soft-chemical interactions. For the less hydrated P123 micellar assemblies, the hydrophobic interactions and strong excluded volume effects probably contribute to stabilization of the protein. The addition of the widely used osmolyte trehalose further delays the protein aggregation and significantly retards the fibril formation through the synergistic inhibitory effects of trehalose and polymer assemblies. The trehalose-bearing pluronic micelles can, therefore, emerge as a potentially efficient inhibitor with great promise in therapeutic applications. The pluronic self-assemblies are also found to be highly effective in protecting the protein from toxicity associated with Cu2+ induced enhanced amyloid fibrillation. The binding of Cu2+ within the hydrated PEO corona makes them inaccessible to protein interactions and fibril formation.

Keywords:  Alzheimer’s disease; amyloid aggregation; fibrillation inhibition; micellar assemblies; neurodegenerative diseases; pluronic copolymers

DOI:  https://doi.org/10.1021/acsabm.5c02236
Biochim Biophys Acta Mol Cell Res. 2026 Feb 17. pii: S0167-4889(26)00020-0. [Epub ahead of print] 120124

Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.

Shannon McMahon, Dezerae Cox, Flora Cheng, Albert Lee, Justin J Yerbury, Heath Ecroyd.

  Maintaining proteome integrity is essential for cellular function and survival. Disruptions in proteostasis lead to the aggregation of proteins into inclusions, a process that underlies many neurodegenerative diseases. To quantitatively assess the proteostasis capacity of neuronal cells, we employed an aggregation-prone double mutant form of firefly luciferase (denoted FlucDM) as a reporter protein. We compared two commonly used neuronal cell lines, mouse neuroblastoma cells (Neuro-2a) and a motor neuron-like hybrid line (NSC-34), to evaluate their ability to prevent the aggregation of proteins into intracellular inclusions. We observed a significantly greater propensity of FlucDM to form inclusions in NSC-34 cells compared to Neuro-2a cells. This suggests a reduced capacity of NSC-34 cells for managing aggregation-prone proteins. Proteomic profiling of FlucDM inclusions purified from both cell types revealed cell-type-specific engagement of the proteostasis machinery with aggregation-prone proteins. Comparing the proteomic profiles of key arms of the proteostasis network between these two cell lines revealed that the endoplasmic reticulum (ER) unfolded protein response is differentially expressed. This study establishes a quantitative platform for assessing cellular proteostasis capacity and underscores the importance of cell-type context in proteome maintenance. These insights have implications for understanding the selective vulnerability of neurons in protein misfolding disorders.

Keywords:  Aggregation index; Inclusions; Neurodegenerative disorders; Protein aggregation; Proteostasis capacity

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120124
Front Radiol. 2026 ;6 1730757

Revealing the invisible: a new imaging paradigm for α-synuclein pathology in Parkinson's disease.

Jian Meng, Xingbo Li.



Keywords:  ASA-PD imaging technique; Parkinson's disease; neurodegenerative biomarkers; single-molecule fluorescence microscopy; α-synuclein oligomers

DOI:  https://doi.org/10.3389/fradi.2026.1730757
Biochemistry (Mosc). 2026 Jan;91(1): 1-16

Diagnostics of Synucleinopathies by Protein Amplification Methods: Methodological and Bibliometric Analysis.

Alexander A Groshkov, Nataliya A Kolotyeva, Pavel P Tregub, Victoria I Zhdankina, Yulia K Komleva, Alla B Salmina, Sergey N Illarioshkin.

  Early preclinical diagnostics of neurodegenerative diseases (synucleinopathies, Alzheimer's disease, etc.) can be achieved through the detection of pathological amyloid aggregates in biological fluids. Protein amplification methods (PMCA, RT-QuIC) have become promising diagnostic tools by offering high sensitivity and specificity for detecting α-synuclein oligomers at the early disease stages and studying the fibril formation kinetics and mechanisms of amyloid aggregation. However, these methods have several significant limitations, as they are technically complex and time-consuming and lack standardized protocols, control samples, and substrates. Despite these challenges, protein amplification methods hold potential as the most productive, accessible, and standardizable diagnostic approaches in synucleinopathies. This review presents the results of bibliometric analysis of publications on the use of protein amplification methods in the diagnostics of synucleinopathies. We also provide a comparative analysis of common RT-QuIC protocols, with special focus on the method principles, approaches for its optimization, types of biological materials, key factors influencing the sensitivity and specificity of this technique, and areas for its improvement.

Keywords:  PMCA; Parkinson’s disease; RT-QuIC; bibliometric analysis; cerebrospinal fluid; dementia with Lewy bodies; early diagnostics; fibrillization; multiple system atrophy; neurodegenerative diseases; protein amplification; synucleinopathies; α-synuclein

DOI:  https://doi.org/10.1134/S000629792560214X
Biochem Biophys Rep. 2026 Mar;45 102487

β-Hydroxybutyrate attenuates glycation-induced structural destabilization and amyloidogenic aggregation in human serum albumin.

Hojjat Mohammadnia, Mousa Bohlooli, Mansour Ghaffari-Moghaddam, Mostafa Khajeh, Fereshteh Taghavi.

  Protein aggregation and amyloid fibril formation are key events in neurodegenerative disorders such as Alzheimer's disease, and are worsened by non-enzymatic glycation, which destabilizes protein structure. Glycation by reducing sugars like glucose produces advanced glycation end products (AGEs), promoting misfolding and aggregation. β-Hydroxybutyrate (BHB), a ketone body with anti-glycation and neuroprotective properties, may counteract these effects. This study examined structural, aggregation, and fibrillar changes of human serum albumin (HSA) after prolonged glucose-induced glycation, and evaluated the modulatory role of BHB via a multi-technique approach. HSA was incubated for 120 days under four conditions: control, BHB alone, glucose alone, and glucose + BHB. Analyses included atomic force microscopy (AFM), circular dichroism (CD) spectroscopy, ANS fluorescence, Thioflavin T (ThT) fluorescence, and Congo Red assays. AGE formation was quantified to link biochemical modifications with aggregation patterns. Glucose treatment markedly increased AGE levels. AFM revealed extensive aggregation and high surface coverage in the glucose group, partially reduced by BHB. CD spectroscopy showed α-helix loss and β-sheet enrichment with glycation, while BHB preserved structure. ANS fluorescence indicated glucose-enhanced hydrophobic exposure, reduced by BHB. ThT and Congo Red assays confirmed less amyloid fibril formation in glucose + BHB samples versus glucose alone. These results suggest that glucose induces marked glycation, structural disruption, and amyloidogenic aggregation in HSA, whereas BHB provides partial protection, likely through structural stabilization and aggregation pathway modulation. BHB may offer therapeutic promise for limiting amyloid-related neurodegenerative diseases.

Keywords:  Advanced glycation end products; Amyloidogenic pathways; Atomic force microscopy; Circular dichroism spectroscopy; Human serum albumin; Neurodegeneration; Structural stabilization; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbrep.2026.102487
Nat Commun. 2026 Feb 18. pii: 1933. [Epub ahead of print]17(1):

Structural defects in amyloid-β fibrils drive secondary nucleation.

Jing Hu, Tom Scheidt, Dev Thacker, Emil Axell, Elin Stemme, Urszula Łapińska, Stefan Wennmalm, Georg Meisl, Samo Curk, Maria Andreasen, Michele Vendruscolo, Paolo Arosio, Anđela Šarić, Jeremy D Schmit, Tuomas P J Knowles, Emma Sparr, Sara Linse, Thomas C T Michaels, Alexander J Dear.

Formation of new amyloid fibrils and oligomers from monomeric protein on the surfaces of existing fibrils is an important driver of many disorders such as Alzheimer's and Parkinson's diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: irregularities in the fibril core structure incorporated during their original assembly. We first demonstrate using the specific inhibitor of secondary nucleation, Brichos, that secondary nucleation sites on Alzheimer's disease-associated fibrils composed of Aβ40 and Aβ42 peptides are rare compared to the number of protein molecules they contain. We then grow Aβ40 fibrils under conditions designed to eliminate most growth defects while leaving the regular fibril morphology unchanged, and confirm the latter using cryo-electron microscopy. We measure both the ability of these annealed fibrils to promote secondary nucleation and the stoichiometry of their secondary nucleation sites, finding that both are greatly reduced as predicted. Re-analysis of published data for other proteins suggests that fibril growth defects may also drive secondary nucleation generally across most amyloids. These findings could unlock structure-based drug design of therapeutics that aim to halt amyloid disorders by inhibiting secondary nucleation sites.

DOI: https://doi.org/10.1038/s41467-026-69377-1
Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00012-4. [Epub ahead of print]45(2): 116934

Nanoscopic tau aggregates are not shared intermediates but disease-specific entities across tauopathies.

Dorothea Böken, Melissa Huang, Yunzhao Wu, Emre Fertan, Matthew W Cotton, Georg Meisl, Jeff Y L Lam, Shaan Baig, James B Rowe, Colin Smith, Annelies Quaegebeur, Dezerae Cox, William A McEwan, David Klenerman.

  Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterize these small tau aggregates from postmortem brain of individuals with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Pick's disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine 356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets.

Keywords:  Alzheimer’s disease; CBD; CP: Neuroscience; PSP; Pick’s disease; Simoa; single molecule; super-resolution microscopy; tau; tau aggregates; tauopathies

DOI:  https://doi.org/10.1016/j.celrep.2026.116934
Neurochem Res. 2026 Feb 17. 51(2): 77

Rotating Magnetic Field Therapy Induces System-Level Neuroprotection in A53T α-Synuclein Transgenic Mice Through Coordinated Suppression of Cellular Stress Pathways.

Umer Anayyat, Muhammad Naeem Kiani, Xueying Mei, Fen Zhang, Aliza Fatima, Zhuohang Yang, Kan Li, Guangsen Zheng, Yunpeng Wei, Xiaomei Wang.

  Current therapeutic strategies for Parkinson's disease (PD) focus exclusively on symptomatic management without addressing underlying disease progression. Despite decades of research emphasizing the enhancement of the cellular defense pathway, disease-modifying treatments remain elusive. We evaluated rotating magnetic field (RMF) therapy in A53T transgenic mice harboring a familial PD-associated mutation. Transgenic and wild-type animals (n = 8 per group) received RMF treatment (4 Hz, 0.4 T, 2 h daily) for six months. Motor function, muscle strength, and neuropathological markers were assessed. Comprehensive transcriptomic and proteomic analyses were performed to elucidate the molecular mechanisms involved. Untreated A53T transgenic mice exhibited progressive motor decline (51% reduction in locomotor activity, 39% decrease in muscle strength) accompanied by the accumulation of pathological α-synuclein aggregates. RMF-treated transgenic mice demonstrated significant functional recovery, with 78% wild-type locomotor activity and 80% normal muscle strength, with a marked reduction in α-synuclein pathology. Molecular profiling revealed unexpected suppression of hyperactivated stress response pathways, including mTOR signaling, autophagy, and oxidative stress responses (NES = -2.05 to -2.65, FDR < 0.01), whereas metabolic defense mechanisms such as glutathione biosynthesis were increased (NES = 2.18, FDR < 0.001).These findings suggest that normalization of aberrant stress signaling through RMF therapy represents a novel disease-modifying strategy with potential applicability to other neurodegenerative disorders characterized by proteostasis dysfunction.

Keywords:  Parkinson’s disease; RMF therapy; neurodegeneration; proteostasis dysfunction; α-synuclein

DOI:  https://doi.org/10.1007/s11064-026-04693-y