bims-proned 2026-07-12 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–07–12
ten papers selected by
Verena Kohler, Umeå University

Phase separation and protein aggregation in neurodegenerative diseases.
Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).
Transthyretin at the crossroads of neurodegeneration: a silent guardian in Parkinson's disease.
Combined Effects of Mutation and Ionic Strength on α-Synuclein Reveal Generic Features of Aggregation-Prone Monomeric States.
Stimulating proteasomal degradation in human proteinopathies.
0N4R Tau aggregates producing morphologically different and structurally similar "on-path" and "off-path" oligomers.
Zinc Differentially Modulates Tau Aggregation, Fibril Morphology, and Prion-like Seeding in a Construct-Dependent Manner.
Annexin A11 and TDP-43: core players in neurodegeneration.
Proteomic and Phosphoproteomic Characterization of Disease-Associated Alterations in Nerve Terminals and Protein Inclusions of Alzheimer's Disease Patients.
The NORAD -pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes.

Biophys Chem. 2026 Jul 04. pii: S0301-4622(26)00111-0. [Epub ahead of print]338 107678

Phase separation and protein aggregation in neurodegenerative diseases.

Hortense de La Seiglière, Ænora Letourneur, François Ichas, Francesca De Giorgi.

  Neurodegenerative diseases such as Alzheimer's, Parkinson's, frontotemporal dementia, and ALS are characterized by amyloid protein aggregation involving intrinsically disordered proteins that are also capable of liquid-liquid phase separation (LLPS). LLPS, known to drive the formation of dynamic membraneless organelles essential for cellular functions, can play a role in limiting fibrillation process or aberrantly transition into solid aggregates under pathological conditions. Here we review how mutations, post-translational modifications, and environmental factors can modulate LLPS of proteins like Tau, TDP-43, FUS, and α-synuclein, potentially regulating amyloid aggregation. We also examine the interplay of these proteins exploring how LLPS and condensate maturation could impinge on the emergence of co-pathologies contributing to disease progression. Finally we discuss emerging therapeutic strategies, aimed at modulating phase separation dynamics.

Keywords:  Amyloid formation; Intrinsically disordered proteins; Liquid-liquid phase separation; Neurodegenerative diseases; Protein aggregation

DOI:  https://doi.org/10.1016/j.bpc.2026.107678
Ann N Y Acad Sci. 2026 Jul;1561(1): e70311

Phase Separation Drives Pathological Aggregation in Neurodegenerative Diseases: A 15-Year Bibliometric Landscape (2009-2024).

Chanyuan Zhang, Siyao Chen, He Zhao, Yan Wang, Lingyan Zhou, Haixia Fan, Yan Sun.

  Liquid-liquid phase separation (LLPS), a biophysical driver of membraneless organelle assembly, is central to pathological aggregation in neurodegenerative diseases. Initially linked to amyotrophic lateral sclerosis (ALS), LLPS dysregulation has now been implicated in Alzheimer's, Parkinson's, and frontotemporal dementia, where aberrant transitions convert dynamic condensates into insoluble fibrils. To systematically map this landscape, we employed CiteSpace-based bibliometrics to analyze 784 Web of Science articles from 2009 to 2024. Our analyses reveal dominant contributions from the United States, China, and Germany, with collaborative networks focusing on protein dynamics. Key hotspots include LLPS-driven aggregation of TARDBP (TDP-43), FUS, and α-synuclein, alongside stress granule dysfunction and nucleocytoplasmic transport defects. Emerging frontiers highlight therapeutic strategies targeting pathological condensates utilizing small-molecule chaperones and posttranslational modification modulators to restore cellular homeostasis. Our findings underscore LLPS as a critical axis bridging molecular pathology and translational innovation. The field is rapidly shifting from mechanistic exploration to therapeutic applications, emphasizing interventions to halt or reverse aggregation. By delineating global trends and changing priorities, our study highlights the transformative potential of phase-targeted interventions and provides a roadmap of groundbreaking interdisciplinary research into neurodegenerative disorders.

Keywords:  Alzheimer's disease; bibliometric analysis; liquid–liquid phase separation; neurodegenerative diseases; pathological aggregation

DOI:  https://doi.org/10.1111/nyas.70311
Metab Brain Dis. 2026 Jul 07. pii: 157. [Epub ahead of print]41(1):

Transthyretin at the crossroads of neurodegeneration: a silent guardian in Parkinson's disease.

Priti Dipa, Khadga Raj Aran.

  Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by disruption of brain homeostasis and degeneration of dopaminergic neurons in the substantia nigra. PD is characterised by motor symptoms, like tremor, rigidity, bradykinesia, and postural instability, as well as non-motor symptoms like cognitive impairment, mood disorders, sleep disturbances, and autonomic abnormalities that significantly affect quality of life. The molecular pathogenesis of PD involves Oxidative stress, neuroinflammation, mitochondrial dysfunction, α-synuclein (α-syn) misfolding and aggregation, insufficient autophagy-lysosomal clearance, and synaptic degeneration, leading to progressive neuronal loss. Transthyretin (TTR), a tetrameric transport protein that is primarily produced in the liver and choroid plexus, is well-known for carrying thyroxine and retinol-binding protein. Experimental studies have shown that TTR can protect neurons by binding misfolded proteins, such as α-syn, decreasing toxic aggregation, regulating oxidative stress responses, and affecting selective autophagic degradation. PD-related changes in TTR expression in brain tissue and cerebrospinal fluid provide strong evidence of TTR's significance as a molecular biomarker and a physiological regulator in the pathogenesis of the disease. This review highlights TTR involvement in neuroinflammation, oxidative stress, and α-syn aggregation, and discusses emerging evidence supporting TTR stabilizers as potential biomarkers and therapeutic targets for modulating disease progression in PD.

Keywords:  Neuroinflammation; Neuroprotection; Parkinson’s disease; Transthyretin; α-synuclein aggregation

DOI:  https://doi.org/10.1007/s11011-026-01907-8
ACS Chem Neurosci. 2026 Jul 07.

Combined Effects of Mutation and Ionic Strength on α-Synuclein Reveal Generic Features of Aggregation-Prone Monomeric States.

Vaishnavi Tammara, Ankita Das, Zion Desai, Atanu Das.

  α-Synuclein (αS) is a highly charged, intrinsically disordered protein (IDP) whose aberrant aggregation is linked to Parkinson's disease (PD). Along with wild-type (WT) αS, five single-point mutants (A30P, E46K, H50Q, G51D, and A53T) are implicated in familial PD. To resolve contradictory experimental observations under varying solution conditions, we investigated how ionic strength modulates the relative aggregation propensity of these six monomeric αS variants using atomistic simulations. Structural and energetic analyses at global, domain, and residue levels revealed that aggregation propensity rankings switch with increasing ionic strength but stabilize beyond physiological concentration, while A53T and H50Q consistently remain highly aggregation-prone. We additionally identified electrostatic-driven decoupling between global and local motions. Aggregation-prone monomers preferentially populate semicompact ensembles with β-sheet propensity, an exposed and stiff N-terminus with fewer interdomain contacts, a flexible yet compact C-terminus, and an NAC domain that is either under-protected and stiff or flexible and poorly hydrated. These monomers further exhibit strong intramolecular stabilization, poor solvation, counterion binding, and subdiffusive collapsing dynamics that may facilitate intermolecular encounters. We justified aggregation propensity trends across ionic strengths, validated physiological trends using a dimer model, suggested a generic monomer-to-aggregate mechanism, and reconciled simulations with experimental variability.

Keywords:  conformational landscape; electrostatic modulation; hydration; intrinsically disordered proteins; molecular flexibility and compaction; polymer dynamics

DOI:  https://doi.org/10.1021/acschemneuro.6c00439
FEBS J. 2026 Jul 07.

Stimulating proteasomal degradation in human proteinopathies.

Maria E Gierisch, Enrica Barchi, Nico P Dantuma.

  The ubiquitin-proteasome system (UPS) comprises hundreds of proteins that orchestrate ubiquitin-dependent proteasomal degradation and represents a powerful therapeutic target for modulating intracellular protein turnover. Due to its central role in preventing the accumulation of misfolded and dysfunctional proteins, enhancing or suppressing UPS activity offers clinical potential across a wide spectrum of diseases. While oncology has successfully capitalized on this vulnerability through the development of proteasome inhibitors for the treatment of hematological malignancies, efforts to generate clinically relevant UPS activators have progressed more slowly. Bridging this therapeutic gap could be particularly beneficial for neurodegenerative diseases and other proteinopathies, where accelerating the removal of misfolded and aggregation-prone proteins may help counteract their progressive accumulation and delay, or prevent the onset of symptoms. In this review, we summarize the progress made so far toward finding strategies to boost UPS function through genetic or small-molecule interventions.

Keywords:  aggregation; neurodegeneration; proteasome; protein degradation; ubiquitin

DOI:  https://doi.org/10.1111/febs.70638
Chem Commun (Camb). 2026 Jul 09.

0N4R Tau aggregates producing morphologically different and structurally similar "on-path" and "off-path" oligomers.

Joshua T Skrehot, Mikhail Matveyenka, Dmitry Kurouski.

We utilized nano-infrared spectroscopy to resolve the morphology and structure of Tau aggregates. We identified "on-path" donut-like aggregates that evolve into fibrils and "off-path" round oligomers that do not. Despite morphological differences, both species share similar β-sheet-rich structures, providing critical insights into the mechanisms of Tau aggregation.

DOI: https://doi.org/10.1039/d6cc02327d
bioRxiv. 2026 Jul 02. pii: 2026.07.01.735859. [Epub ahead of print]

Zinc Differentially Modulates Tau Aggregation, Fibril Morphology, and Prion-like Seeding in a Construct-Dependent Manner.

Emma L Poirier, Alyssa Stainton, Oskar Simon, Suhana S Mittal, Ana B Varona Ortiz, Sally A Kim, Jennifer N Rauch.

The role of tau fibril structure in seeding and propagation of aggregation remains a central unresolved question in tauopathy biology. While non-proteinaceous cofactors are increasingly observed in patient-derived tau filaments, whether they actively determine fibril structure and function is not well understood. Here, we show that zinc, a divalent cation dysregulated in Alzheimer's disease (AD), can drive fundamentally different aggregation and seeding outcomes depending on tau sequence context. Using heparin-free conditions, we compared full-length 2N4R tau (residues 1-441) with an AD-tau fragment (residues 304-380) corresponding to the ordered fibril core. Strikingly, Zn 2+ exerted opposite effects on these constructs: it accelerated aggregation, increased fibril length, and enhanced cellular seeding for AD-tau, while slowing aggregation, shortening fibrils, and suppressing seeding for full-length tau. These findings demonstrate that cofactor effects are not intrinsic properties of the cofactor itself, but emerge from its interplay with tau sequence and conformational constraints. More broadly, our results support a model in which small-molecule cofactors act as active architects of fibril structure and function, suggesting that chemically distinct environments could generate structurally and biologically distinct tau strains in disease.

DOI: https://doi.org/10.64898/2026.07.01.735859
Acta Neuropathol. 2026 Jul 07. pii: 4. [Epub ahead of print]152(1):

Annexin A11 and TDP-43: core players in neurodegeneration.

Courtney L Smith, John L Robinson, Edward B Lee.

  Annexin A11 (ANXA11) is a Ca2⁺-dependent phospholipid-binding protein that has recently emerged as a key player in neurodegeneration. Rare pathogenic ANXA11 variants were initially identified in cases of amyotrophic lateral sclerosis (ALS). Since then, ANXA11 has been linked to a broader spectrum of related neurodegenerative diseases. Two independent studies demonstrated that ANXA11 co-aggregates with TDP-43 in all cases of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C, with cryo-EM revealing heteromeric ANXA11-TDP-43 filaments. These discoveries support the direct pathological interaction between the two proteins as an important feature of FTLD-TDP type C. We also described secondary ANXA11 pathology in related neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE), and more rarely in ALS and FTLD-TDP types A and B. ANXA11 and TDP-43 co-aggregates are also a feature of a FTLD-TDP associated with primary lateral sclerosis. These advances have renewed interest in ANXA11 as a major player in ALS/FTLD pathogenesis in both genetic and sporadic neurodegenerative diseases. In this review, we summarize ANXA11 pathology across genetic and sporadic cases, highlighting its heterogeneous overlap with TDP-43 pathology. We synthesize current knowledge of ANXA11's physiological roles in phase separation, membrane repair, and RNA granule dynamics, integrating emerging evidence on how disruption of these processes may promote pathological aggregation and toxicity. Finally, we outline priorities for future research, with particular emphasis on elucidating ANXA11's mechanistic connection to TDP-43.

Keywords:  ALS; Annexin A11; FTLD-TDP; Neurodegenerative disease; TDP-43

DOI:  https://doi.org/10.1007/s00401-026-03043-0
J Proteome Res. 2026 Jul 07.

Proteomic and Phosphoproteomic Characterization of Disease-Associated Alterations in Nerve Terminals and Protein Inclusions of Alzheimer's Disease Patients.

Sofie B Elmkvist, Camilla K Thygesen, Pia Jensen, Maria Pihl, Kristine K Freude, Bente Finsen, Martin R Larsen.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, protein aggregation, and widespread molecular alterations in the brain. In this study, we applied quantitative mass spectrometry-based proteomics and phosphoproteomics to characterize synaptosomes and sarkosyl-insoluble protein inclusions from the post-mortem frontal lobes of AD and control cases. We identified >3700 proteins across both fractions, revealing AD-associated changes in synaptic composition and phosphorylation patterns. Proteomic analyses indicated mitochondrial deficits and disruptions in vesicle trafficking within synapses, whereas insoluble protein inclusions showed an accumulation of spliceosomal components and glial activation markers as well as an enrichment of N-terminally truncated amyloid beta peptides in AD cases, suggesting involvement of postfibrillar processing events mediated by specific proteases in amyloid plaque pathology. Phosphoproteomic analysis revealed extensive alterations in pathways regulating vesicle trafficking, Golgi homeostasis, and synaptic function. We observed increased tau phosphorylation at AD-associated sites in insoluble inclusions and distinct phosphorylation changes in synaptic tau, particularly at S285 and S305, suggesting altered tau function and aggregation properties. These findings provide new molecular insights into AD-related nerve terminal composition and protein aggregation, advancing our understanding of disease-associated changes at the subcellular level.

Keywords:  Alzheimer disease; neocortex; phosphorylation; protein aggregation; proteomics; sarkosyl-insoluble fraction; synaptosomes; tau phosphorylation

DOI:  https://doi.org/10.1021/acs.jproteome.5c01160
bioRxiv. 2026 Jul 03. pii: 2026.06.30.735697. [Epub ahead of print]

The NORAD -pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes.

Dominantly Inherited Alzheimer Network

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimer's disease and Parkinson's disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD -associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD -pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD -pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

DOI: https://doi.org/10.64898/2026.06.30.735697