bims-proned 2026-10-18 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–10–18
nine papers selected by
Verena Kohler, Umeå University

Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.
Disarming CH25H to clear α-synuclein.
From dynamic condensates to pathological assemblies: the phase behavior of tau and α-synuclein.
Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.
Studies on topological maturation of α-synuclein fibrils in Parkinson's disease: Insights from persistent homology and SARS-CoV-2 acceleration of aggregation.
A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.
The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.
Stress granules at the crossroads of the proteostasis network.
Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.

Int J Biol Macromol. 2026 Oct 13. pii: S0141-8130(26)04795-1. [Epub ahead of print]384(Pt 2): 154845

Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.

Kamile Mikalauskaite, Dominykas Veiveris, Vytautas Smirnovas, Mantas Ziaunys.

  Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.

Keywords:  Alpha-synuclein aggregation; Alpha-synuclein oligomers; Fibril structures; Liquid-liquid phase separation

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154845
Trends Mol Med. 2026 Oct 14. pii: S1471-4914(26)00231-5. [Epub ahead of print]

Disarming CH25H to clear α-synuclein.

Guangyu Wu, Qin Wang.

  α-Synuclein (α-Syn) accumulation is a defining feature of Parkinson's disease (PD). Zhang et al. identify cholesterol 25-hydroxylase (CH25H) as an astrocytic inhibitor of p62-dependent α-Syn degradation. Disrupting the CH25H-p62 interaction facilitates α-Syn clearance via autophagy and improves PD-like phenotypes, suggesting a previously unrecognized nonenzymatic function for CH25H with therapeutic potential.

Keywords:  astrocytes; autophagy; cholesterol 25-hydroxylase; p62; synucleinopathy

DOI:  https://doi.org/10.1016/j.molmed.2026.09.015
Front Mol Neurosci. 2026 ;19 1965177

From dynamic condensates to pathological assemblies: the phase behavior of tau and α-synuclein.

Suelen Camargo, Kevin Novelo, Scott D Ryan.

  Neurons rely on precise protein folding, trafficking, and turnover to maintain synaptic function. Disruption of proteostasis promotes misfolded proteins that impair axonal transport, mitochondrial function, and signalling, contributing to neuronal loss. Although neurodegeneration has traditionally focused on stable amyloid deposits, many disease-associated proteins contain intrinsically disordered regions (IDRs) that can organize through liquid-liquid phase separation (LLPS). LLPS concentrates proteins and nucleic acids into dynamic condensates that regulate cellular processes, but these adaptive interactions can also promote condensate aging and less reversible, aggregation-prone states. Here, we review how sequence-encoded properties of tau and α-synuclein (α-syn) link physiological condensation to pathological protein assembly, while emphasizing that LLPS and amyloid formation are related but not obligatorily linked.

Keywords:  LLPS; amyloid aggregation; amyloid generation; biomolecular condensates; synuclein alpha; tau

DOI:  https://doi.org/10.3389/fnmol.2026.1965177
Microb Cell. 2026 ;13 358-377

Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.

Joan Castells-Ballester, Natalia Shcherbik.

  Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.

Keywords:  Bfr1; Saccharomyces cerevisiae; Scp160/Vigilin; TDP-43; endoplasmic reticulum; protein aggregation; proteostasis; proteotoxicity

DOI:  https://doi.org/10.15698/mic2026.10.888
J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261464972

Studies on topological maturation of α-synuclein fibrils in Parkinson's disease: Insights from persistent homology and SARS-CoV-2 acceleration of aggregation.

Pranathi Jalapally, Lakshmi Sowmya Emani, Sminu Izudheen, K S Jagannatha Rao.

   Background: Parkinson's disease (PD) is marked by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-syn) into amyloid fibrils and Lewy bodies. These aggregates impair synaptic function, disrupt proteostasis, compromise mitochondrial health, and drive neuroinflammation and oxidative stress. Clinical observations during the COVID-19 pandemic revealed accelerated motor deterioration and higher mortality among PD patients following SARS-CoV-2 infection, pointing to potential overlapping mechanisms with Alzheimer's disease, including protein misfolding, chronic inflammation, and oxidative damage.
Objective: This study aims to investigate how the SARS-CoV-2 N-protein may accelerate α-syn aggregation using computational approaches.
Methods: We employed a multimodal, label-free computational pipeline inspired by TopoBind to examine the topological maturation of patient-derived α-syn fibrils across preclinical (PDB 7V47, 8H03), mid-stage (7XO0, 7XO1), and late-stage (8H04, 7V48) PD phases. Per-residue features were extracted using 640-dimensional evolutionary scale modeling (ESM)-2 embeddings, solvent-accessible surface area, and persistent homology based on Vietoris-Rips filtration of Cα coordinates (r = 0-20 Å, persistence threshold > 0.8 Å). Predictions were validated using PyRosetta InterfaceAnalyzerMover, PRODIGY (ΔG and Kd), and normal mode analysis.
Results: The pipeline successfully identified key protein-protein interface residues on α-syn fibrils, achieving 74-92% overlap with PyRosetta results. Conserved interaction hotspots were located primarily in the non-amyloid component region, protofilament interfaces, and hydrophobic grooves.
Conclusions: Our findings demonstrate that fibril maturation involves progressive expansion of binding interfaces, offering a plausible topological mechanism by which SARS-CoV-2 N-protein can promote pathogenic α-syn conformers and contribute to long-term neurological complications following infection.

Keywords:  Alzheimer's disease; PRODIGY; Parkinson's disease; PyRosetta; SARS-CoV-2 n-NTD; TopoBind; graph neural network; neurodegeneration; persistent homology; protein–protein interface; α-synuclein fibrils

DOI:  https://doi.org/10.1177/25424823261464972
bioRxiv. 2026 Oct 01. pii: 2026.09.30.755777. [Epub ahead of print]

A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.

Tarah Krishingner, Sarah R Fausett.

  Protein aggregates are a diverse array of intra- and extracellular structures containing misfolded proteins with limited macromolecular movement. Protein aggregation is induced by aging and cellular stress and is a hallmark of neurodegenerative diseases including Huntington's, Alzheimer's, and Parkinson's. Fluorescent tools to visualize global protein aggregation in whole organisms are, therefore, important for screening genes and compounds that may reduce or alter protein aggregation in connection with improved health outcomes. Fluorescent probes that report low fluidity structures in cells, such as molecular rotor dyes, are gaining popularity and overcome certain limitations of targeted markers such as tagged proteins or antibodies. However, permeability has been a key barrier preventing widespread use of such probes in whole organisms, including in C. elegans. To achieve visualization of non-specific protein aggregates in whole C. elegans nematodes without the need for strain engineering, we have developed a simple soaking protocol. Our protocol overcomes the permeability limitations of the commercially available molecular rotor dye, Proteostat, enabling widespread labeling of protein aggregates in live and post-fixed worms. Here, we present our novel approach and demonstrate quantification of protein aggregates in multiple tissues to detect differences in protein aggregation due to both genotype and treatment effects. We also outline anticipated future applications for this protocol, including its adaptation for other dyes, as well as limitations and special considerations for its use.

Keywords:  C. elegans; Proteostat; live staining protocol; protein aggregation

DOI:  https://doi.org/10.64898/2026.09.30.755777
Metab Brain Dis. 2026 Oct 14. pii: 235. [Epub ahead of print]41(1):

The small giant actor in the pathogenesis of neurodegenerative diseases: Microtubules.

Aslı Aksoy Gündoğdu, Neslihan Gücüyener Özkan, Demet Özbabalık Adapınar.

  Neurodegenerative diseases are a clinically and pathologically diverse group of disorders characterized by progressive neuronal dysfunction, synaptic impairment, and neuronal loss. Although research has traditionally focused on disease-associated protein misfolding and aggregation, increasing evidence implicates abnormalities of cytoskeletal organization and intracellular transport in several neurodegenerative conditions. Microtubules contribute to neuronal polarity, axonal and dendritic transport, organelle distribution, and synaptic maintenance. These functions are regulated in part by tubulin isotypes, post-translational modifications collectively described as the tubulin code, microtubule-associated proteins, and molecular motors. This narrative review examines evidence linking alterations in these processes with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. We summarize proposed interactions among microtubule instability, impaired axonal transport, mitochondrial dysfunction, and disease-associated proteins, including tau, α-synuclein, mutant huntingtin, TDP-43, and prion protein. Evidence connecting tau pathology with microtubule dysfunction is comparatively well established in Alzheimer's disease and MAPT-related tauopathies, whereas findings in other disorders are more heterogeneous and are frequently derived from cellular or animal models. We also discuss emerging experimental approaches, candidate biomarkers, and investigational microtubule-directed treatments. However, no tubulin-specific biomarker or microtubule-targeted disease-modifying treatment discussed in this review has yet been clinically validated. Overall, microtubule dysfunction may represent one component of broader, disease-specific pathological networks rather than a universal primary cause of neurodegeneration. Further longitudinal and clinical studies are needed to determine whether microtubule-related alterations act as causes, consequences, or modifiers of disease progression.

Keywords:  Axonal transport; Microtubule dynamics; Neurodegeneration; Tauopathy; Tubulin code; α-synuclein

DOI:  https://doi.org/10.1007/s11011-026-02001-9
RNA Biol. 2026 Dec;23(1): 1-22

Stress granules at the crossroads of the proteostasis network.

Rachel Kim, Erika N Calle Urgiles, Stephanie L Moon.

  The proteostasis network maintains cell function by safeguarding the proteome through the coordinated actions of protein synthesis, quality control, and degradation machinery including chaperones and the ubiquitin-proteasome system. Proteostasis collapse and activation of the integrated stress response (ISR) occur in ageing and neurodegeneration. Upon proteotoxic stress, translation suppression during the ISR drives the assembly of non-translating mRNAs into biomolecular condensates called stress granules. Stress granules act as a double-edged sword in the proteostasis network, serving beneficial or detrimental roles through their effects on translation, protein quality control, and protein aggregation. In this review, we discuss how protein synthesis, quality control, and degradation factors regulate stress granule dynamics, and conversely how stress granules impact proteostasis. While stress granules may initially protect cells by sequestering misfolded, aggregation-prone proteins and regulating translation, they may evolve into sites of pathological aggregation. Clarifying these intersections may reveal therapeutic strategies for neurodegeneration and other disease processes.

Keywords:  Proteostasis; integrated stress response; protein quality control; stress granules; translation

DOI:  https://doi.org/10.1080/15476286.2026.2731904
bioRxiv. 2026 Oct 01. pii: 2026.09.23.753732. [Epub ahead of print]

Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life.

S MurthyGowda, K Huyghue, B Castillo, F Gugala, W Li, J Dubnau.

A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1-8]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in Drosophila . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.

DOI: https://doi.org/10.64898/2026.09.23.753732