bims-proned 2026-08-09 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–08–09
ten papers selected by
Verena Kohler, Umeå University

Mechanistic insights into the inhibition of α-synuclein aggregation by sugar-based nanoparticles.
Terbutaline selectively reduces non-fibrillar α-synuclein aggregates and oxidative stress without affecting liquid-liquid phase separation or fibrillogenesis.
Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.
Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.
NanoBiT screening identifies the azaoxafluorene VT11 as potent tau interaction inhibitor.
No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.
Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.
A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.
Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.

Biochim Biophys Acta Proteins Proteom. 2026 Aug 02. pii: S1570-9639(26)00045-2. [Epub ahead of print] 141168

Mechanistic insights into the inhibition of α-synuclein aggregation by sugar-based nanoparticles.

Danish Alam, Tanzeel Khan, Iqra Sadiq, Priyanka Mudad, Malik Aquib Javed, Tokeer Ahmad, Asimul Islam, Meryam Sardar.

  The pathological accumulation of α-synuclein (α-syn) into amyloid fibrils is a key hallmark of Parkinson's disease and related synucleinopathies. Inhibiting the early stages of α-syn aggregation remains a major therapeutic challenge. In this work, we report the fabrication and investigation of five sugar-based nanoparticles (NPs), including glucose, fructose, maltose, sucrose, and trehalose, and their ability to inhibit α-synuclein aggregation. Using a combination of biophysical strategies, comprising thioflavin-T fluorescence, dynamic light scattering, circular dichroism, and confocal microscopy, we illustrate that sugar NPs prevent β-sheet formation and the growth of α-syn fibrils in a concentration-dependent manner. Isothermal titration calorimetry revealed spontaneous, high-affinity interactions between α-syn and sugar NPs, suggesting direct binding to aggregation-prone regions. Importantly, cytotoxicity assays using SH-SY5Y neuroblastoma cells showed that NP-treated α-syn aggregates exhibited significantly reduced neurotoxicity. Collectively, these findings demonstrate that sugar-derived nanoparticles act as potent inhibitors of α-syn aggregation during the lag phase, thereby stabilizing non-toxic conformers. These results highlight the promise of sugar-based nanostructures as biocompatible and mechanistically active molecules for modulating synucleopathies associated with various neurodegenerative disorders.

Keywords:  Aggregation; Neurodegenerative disorders; Sugar nano-osmolytes; α-synuclein

DOI:  https://doi.org/10.1016/j.bbapap.2026.141168
Eur J Pharmacol. 2026 Aug 05. pii: S0014-2999(26)00676-X. [Epub ahead of print] 179194

Terbutaline selectively reduces non-fibrillar α-synuclein aggregates and oxidative stress without affecting liquid-liquid phase separation or fibrillogenesis.

Soumojit Biswas, Nimisha A Mavlankar, Asish Pal, Ipsita Roy.

  Aggregation of α-synuclein is intricately linked to Parkinson's disease (PD), progressing through liquid-liquid phase separation (LLPS) to toxic protofibrils and mature amyloid fibrils. Identifying compounds that selectively modulate toxic aggregation intermediates without interfering with normal cellular phase separation is a critical therapeutic goal. This study investigated the impact of terbutaline, a β2-adrenergic agonist, on the liquid-liquid phase separation, aggregation behaviour, cytotoxicity and oxidative stress induced by WT α-SYN and its variants. Terbutaline did not affect the size or physical properties of α-SYN condensates or alter fibril formation, as evidenced by unchanged Th T fluorescence and fluorescence polarization values. However, it significantly reduced the number of condensates and total aggregates, particularly amorphous moiety, in a concentration-dependent manner. This selective inhibition did not influence survival of SH-SY5Y cells but significantly reduced α-SYN-induced superoxide generation in rat RBCs-by up to 26% for WT and 53% for CT α-SYN aggregates. Distinct changes were observed in the oligomers formed by WT α-SYN and CT α-SYN. Direct interaction of terbutaline with both WT α-SYN and CT α-SYN was confirmed by isothermal titration calorimetry, with a stronger binding affinity observed for the CT α-SYN. Transmission electron microscopy showed discrete morphological changes in aggregate structure with terbutaline, supporting a shift away from toxic polymorphs. These findings highlight terbutaline's role as a potential modulator of early aggregation toxicity, warranting further exploration into structurally related compounds for therapeutic development in synucleinopathies.

Keywords:  Liquid condensates; Phase separation; Protein aggregation; Protofibrils; Synuclein mutants; Terbutaline

DOI:  https://doi.org/10.1016/j.ejphar.2026.179194
Aging Dis. 2025 Aug 06. 17(5): 2468-2489

Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.

Khoshnur Jannat, Sang-Bong Lee, Hong-Ryeol Jung, Rengasamy Balakrishnan, Yon-Suk Kim, Mujeeb Ur Rahman, Dong-Kug Choi.

Parkinson's disease is a neurodegenerative condition characterized by the accumulation of misfolded and aggregated α-synuclein in Lewy bodies and neurites. These protein aggregates contribute to neurodegeneration and motor symptoms such as bradykinesia, rigidity, and tremor. While the ubiquitin-proteasome system degrades soluble α-synuclein, aggregated and oligomeric forms are primarily cleared via the autophagy-lysosomal pathway. Mutations of the SNCA gene exacerbate α-synuclein aggregation and significantly impair its clearance, highlighting the importance of targeting toxic α-synuclein species. Strategies such as promoting autophagosome formation via 5'-AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) or facilitating autophagosome maturation via RAB7-a member of the RAS oncogene family-and related effectors, have shown promise in enhancing autophagy and reducing α-synuclein pathology. Pharmacological agents such as rapamycin, trehalose, and nilotinib have demonstrated preclinical efficacy in enhancing α-synuclein clearance and alleviating disease features. Concurrently, immunotherapy approaches, including passive and active immunization, aim to enhance the immune system's ability to recognize and eliminate toxic α-synuclein species. Emerging strategies such as peptide-based therapies aim to inhibit aggregation or promote degradation of α-synuclein. At the same time, nanotechnology enables the targeted delivery of therapeutic agents across the blood-brain barrier with improved efficiency. Additionally, novel AUTOTAC (autophagy-targeting chimera) platforms offer a precision strategy to tag α-synuclein for autophagic degradation. This review explores many advances in autophagy-mediated aggregated α-synuclein clearance, emphasizing its potential as a therapeutic strategy to address the limitations of current symptomatic treatments and slow the progression of Parkinson's disease.

DOI: https://doi.org/10.14336/AD.2025.0642
Mol Cell Biol. 2026 Aug 04. 1-19

Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.

Masahiko Takahashi, Takayuki Abe, Masahiro Fujii.

  Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; stress granule; ubiquitin-specific protease 10

DOI:  https://doi.org/10.1080/10985549.2026.2705871
Commun Chem. 2026 Aug 01. pii: 263. [Epub ahead of print]9(1):

Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.

Andreas Carlsson, Emil Axell, Johan Wallerstein, Dev Thacker, Ulf Olsson, Sara Linse.

The aggregation of the tau protein into intraneuronal fibrillar tangles is closely associated with the pathology of Alzheimer's disease. The endogenous defense system against this process includes molecular chaperones, among which DNAJB6b has emerged as a key component. Using a tau model system comprising the tau fragment 304-380C322S, which spans the amyloidogenic core of ex vivo Alzheimer's disease fibrils, we investigated the impact of DNAJB6b on tau fibril formation. Here, we show that DNAJB6b potently delays tau aggregation by co-assembling with small tau aggregates and by binding to mature fibrils, thereby reducing their ability to catalyze further fibril growth. This interplay between tau and the chaperone results in greatly reduced fibril formation rate and a lower final fibril mass, which we interpret as increased tau solubility. Moreover, solution-state NMR spectroscopy confirms that DNAJB6b does not interact with tau monomers.

DOI: https://doi.org/10.1038/s42004-026-02108-1
Sci Rep. 2026 Aug 04. pii: 24013. [Epub ahead of print]16(1):

NanoBiT screening identifies the azaoxafluorene VT11 as potent tau interaction inhibitor.

Niya Ma, Jens Stieler, Isabel Hilbrich, Tim Vogel, Andreas Hilgeroth, Detlef Briel, Michael Schaefer, Max Holzer, Moritz Metelmann.

  Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the Spectrum Collection and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (NanoLuciferase Binary Technology). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer's disease and other tauopathies.

Keywords:  Azaoxafluorene VT11; NanoBiT assay; RT-QuIC; Tau-tau interaction

DOI:  https://doi.org/10.1038/s41598-026-65368-w
J Pept Sci. 2026 Sep;32(9): e70118

No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.

Tatsuhito Matsuo, Isao Suetake, Mariko Kimura, Satoshi Hashimoto, Koichi Matsuo, Sakiko Matsumoto, Shinji Hirotsune, Hironobu Hojo.

α-Synuclein (αSyn) is a major component of pathogenic Lewy bodies and Lewy neurites and is closely associated with Parkinson's disease. Among the various posttranslational modifications of αSyn, several have been implicated in the degeneration of dopaminergic neurons and are thought to promote Parkinson's disease through enhanced misfolding, aggregation, and accumulation of αSyn. Two such modifications, phosphorylation at Ser129 (S129Phos) and hydroxylation at Tyr136 (Y136DOPA), exert distinct effects on αSyn aggregation: S129Phos has been reported to either inhibit or promote aggregation, whereas Y136DOPA induces the formation of short oligomeric species. To gain insight into the molecular basis underlying the initiation of αSyn multimerization, we semisynthesized αSyn carrying either S129Phos or Y136DOPA and prepared recombinant unmodified full-length αSyn as a control. Vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy revealed that these αSyn variants in their monomeric states possessed essentially identical secondary structures. These results suggest that the modifications themselves do not induce significant secondary structural changes in monomeric αSyn.

DOI: https://doi.org/10.1002/psc.70118
Neurotherapeutics. 2026 Aug 05. pii: S1878-7479(26)00140-6. [Epub ahead of print] e00970

Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.

Siew Chin Chan, Chih-Wei Tung, Chih-Yi Chang, Ching-Chun Su, Yi-Ching Chen, Po-Ming Wu, Chia-Yu Tung, Shih-Feng Chen, Hsiao-Ying Kuo, Pei-Hsun Cheng, Chuan-Mu Chen, Shang-Hsun Yang.

  Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.

Keywords:  Huntington’s disease; Isg15; Stat1; Ubiquitin-proteasome system; Wild-type C9orf72

DOI:  https://doi.org/10.1016/j.neurot.2026.e00970
bioRxiv. 2026 Jul 10. pii: 2026.07.07.735601. [Epub ahead of print]

A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.

Pragati, Erin E Congdon, Yixiang Jiang, Hediye Erdjument-Bromage, Huai-Wei Huang, Ruimin Pan, Isabella S Marchal, Xiang-Peng Kong, Thomas A Neubert, Hyung Don Ryoo, Einar M Sigurdsson.

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.

DOI: https://doi.org/10.64898/2026.07.07.735601
N Biotechnol. 2026 Aug 07. pii: S1871-6784(26)00097-X. [Epub ahead of print]

Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.

Maya Rabinovich, Shiran Lacham-Hartman, Niv Papo.

  Alzheimer's disease is associated with the aggregation of amyloid-β42 (Aβ42) into species of varying sizes, with intermediate oligomers being the most neurotoxic. We recently reported that amyloid precursor protein inhibitor (APPI), a Kunitz-type protein, and a cyclic peptide derived from its β-domain reduced Aβ42-mediated neurotoxicity, the former by reducing Aβ42 aggregation and formation of toxic Aβ42 oligomers, and the latter by promoting Aβ42 aggregation to form fibrils rather than the neurotoxic Aβ42 oligomers. To address the question of whether these two inhibition mechanisms are controlled by the structure or the amino acid sequence of the protein/peptide, we exploited three Kunitz-type proteins, bikunin, bovine pancreatic trypsin inhibitor (BPTI) and tissue factor pathway inhibitor (TFPI) - chosen for their similar β-strand-rich structures but different sequences to one another and to APPI - and also short peptides that mimic their β-domains, in either cyclic or linear conformation. In-vitro studies showed that the formation of Aβ42 aggregates was reduced by the three Kunitz-type proteins and by their derived cyclic peptides, but not by the linear counterparts of the cyclic peptides. In SH-SY5Y neuroblastoma cells, the Kunitz-type proteins and the cyclic (but not the linear) peptides reduced the intracellular and extracellular accumulation of Aβ42 aggregates, respectively. Both the Kunitz-type proteins and the cyclic peptides inhibited Aβ42-induced mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. Overall, this study thus reveals the potential of the β-hairpin structure, whether as a segment within the Kunitz-type proteins or isolated as a cyclic peptide, to interact with Aβ42, thereby reducing Aβ42 aggregation and hence its neurotoxicity.

Keywords:  Alzheimer's disease; Aβ42 aggregation; BPTI; Kunitz-type proteins; TFPI; bikunin; neurotoxicity; β-hairpin

DOI:  https://doi.org/10.1016/j.nbt.2026.08.001