bims-proned 2025-10-26 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–10–26
twelve papers selected by
Verena Kohler, Umeå University

Beyond prion-like spreading in neurodegenerative disease.
Rotenone accelerates endogenous α-synuclein spreading and enhances neurodegeneration in an intra-striatal α-synuclein preformed fibril injected mouse model of Parkinson's disease.
ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.
The Effect of SARS-COV-2 Protein Fragments on the Dimerization of α-Synuclein.
Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.
Olive polyphenols as modulators of amyloid aggregation: mechanisms and implications for neurodegenerative diseases.
Structure and Molecular Basis for Inhibiting Human SOD1 Aggregation by a Promising Decan Derivative Modulator: A Potential Therapeutic Strategy for Treating Amyotrophic Lateral Sclerosis (ALS).
On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.
Decoding Glycosylation in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Opportunities.
Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular Docking Studies Targeting Toxic Polyglutamine (PolyQ) Repeats in Huntington's Disease.
Metal ions control amyloid catalysis.
Therapeutic Horizons for Parkinson's Disease: Current Relevance of PNA5 in Memory and Cognition.

Alzheimers Dement. 2025 Oct;21(10): e70789

Beyond prion-like spreading in neurodegenerative disease.

Georg Meisl, James B Rowe, David Klenerman.

  To design effective therapies for neurodegenerative diseases, it is critical to understand the processes that trigger protein aggregation in sequential brain regions as the disease progresses. Aggregates formed in many neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are capable of seeding, leading to the proposal to regard them all as prion-like. We here argue that the utility of this classification is limited; the terms protein misfolding and aggregation-related diseases describe the general class of diseases, and the connotation of prion-like that the spreading of infectious prions is the rate-limiting process narrows the view of possible mechanisms. Instead, we suggest four factors along which to compare different diseases and model systems, providing a clearer basis to consider the different ways in which pathology can spread, account for factors beyond the aggregating protein, such as declining protein homeostasis with age, and understand the differences between model systems and human disease. HIGHLIGHTS: Four aspects by which to classify neurodegenerative diseases are proposed. Aggregates in health and inflammation are important factors. Prion-like spreading classification is not sufficient to capture the necessary nuance. Different diseases and model systems are dominated by different aspects.

Keywords:  aggregate removal; disease mechanisms; neurodegeneration; prion‐like; protein aggregation; protein homeostasis

DOI:  https://doi.org/10.1002/alz.70789
Front Cell Neurosci. 2025 ;19 1624593

Rotenone accelerates endogenous α-synuclein spreading and enhances neurodegeneration in an intra-striatal α-synuclein preformed fibril injected mouse model of Parkinson's disease.

Engila Khan, Nada Radwan, Mustafa T Ardah, Tohru Kitada, M Emdadul Haque.

  Prominent histopathological features of Parkinson's disease (PD) include the presence of Lewy bodies, intra-neural protein aggregates mainly composed of α-synuclein (α-syn), and cell death of dopaminergic neurons. Epidemiological studies have revealed a correlation between exposure to environmental neurotoxins, such as rotenone, and an increased risk of developing PD. In this study, we evaluated the role of rotenone in α-syn spreading and accumulation, with the aim of developing a mouse model of accelerated PD. Human α-synuclein pre-formed fibrils (PFF) were injected into the mouse striatum by stereotactic surgery. Rotenone (2.5 mg/kg-body-weight) was administered intraperitoneally once daily for four consecutive weeks one day or three weeks after the PFF injection. Brains were collected twenty-four hours after the last injection for immunohistochemical analysis. In this study, rotenone significantly synergized PFF induced α-syn spreading, neuroinflammation, in addition to augmented loss of dopaminergic neurons along the nigrostriatal pathway.

Keywords:  Parkinson’s disease; mouse model; neurodegeneration; rotenone; α-synuclein

DOI:  https://doi.org/10.3389/fncel.2025.1624593
Sci Adv. 2025 Oct 24. 11(43): eado4330

ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.

Qiwang Xiang, Yuning Lu, Hongjin Wang, Hao Chen, Peng Chen, Xiaofeng Zhao, Larissa Cortes Morales, Yiwei Yang, Junqin Yang, Tao Zhang, Jiou Wang.

Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes fragmentation of both the cis- and trans-Golgi networks, disrupting protein sorting and impairing lysosomal functions. The ITCH-dependent lysosomal dysfunction compromises the clearance of misfolded proteins associated with several neurodegenerative diseases. Inhibition of ITCH protects against proteotoxicity in both mammalian neurons and Drosophila models of neurodegeneration. The accumulation of ITCH in patients with ALS and AD is attributed to up-regulation of the ubiquitin-specific protease USP11, which deubiquitinates and stabilizes ITCH. These results uncover a pathogenic pathway regulating Golgi integrity and contributing to the development of neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.ado4330
ACS Chem Neurosci. 2025 Oct 22.

The Effect of SARS-COV-2 Protein Fragments on the Dimerization of α-Synuclein.

Lucy M Coleman, Ulrich H E Hansmann.

  There is evidence that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein (αS), the main component of brain-located amyloids whose presence is connected with Parkinson's Disease (PD). Using molecular dynamics simulations, we showed in earlier work that SARS-COV-2 protein fragments shift the ensemble of αS chains toward more aggregation-prone conformations. However, the mechanism by which these chains assemble into fibrils, the presumed neurotoxic agents in PD, is not clear. The first step on that route is the formation of dimers. For this reason, we have now, using again molecular dynamics simulations, studied how the fragment 194FKNIDGYFKI203 (FI10) of the SARS-COV-2 spike protein and the fragment 54SFYVYSRVK62 (SK9) of the envelope protein alter the ensemble of α-synuclein dimers. Our simulations suggest a differential stabilization of such dimers that would preferentially seed rod-like fibrils over the competing twister-like structures.

Keywords:  Parkinson’s disease; SARS-CoV-2; amyloid aggregation; dimers; molecular dynamics simulations; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00635
Signal Transduct Target Ther. 2025 Oct 23. 10(1): 358

Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.

Omer Faruk Kuzu, Lars Jørgen Tvenge Granerud, Fahri Saatcioglu.

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comprehensive and multidimensional analysis of protein folding biology, tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics. We explore the historical progression of protein folding research, including landmark discoveries of secondary structure, chaperone biology, and energy landscape theory. We detail the roles of key molecular chaperones across cytosolic, mitochondrial, and endoplasmic reticulum compartments, emphasizing their collaborative actions in protein folding and quality control. We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences, paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity. We then examine therapeutic innovations targeting proteostasis, including chaperone modulators, proteostasis pathway inhibitors, and emerging strategies to increase proteome resilience. By consolidating insights at the molecular, cellular, and systems levels, this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.

DOI: https://doi.org/10.1038/s41392-025-02439-w
Food Funct. 2025 Oct 20.

Olive polyphenols as modulators of amyloid aggregation: mechanisms and implications for neurodegenerative diseases.

Ana Cañuelo.

The Mediterranean diet is well known for its role in promoting healthy aging and reducing the risk of chronic diseases, with extra virgin olive oil (EVOO) recognized as a key contributor to these benefits. Among EVOO's constituents, minor phenolic compounds have emerged as principal mediators of its biological activity. Given the pivotal role of amyloid aggregation in protein misfolding disorders (PMDs), considerable research over the past two decades has focused on amyloidogenic proteins and the discovery of natural compounds capable of modulating their aggregation. This review summarizes current evidence on the anti-amyloidogenic properties of olive-derived polyphenols, emphasizing their mechanisms of action and therapeutic relevance in two major neurodegenerative diseases, Alzheimer's and Parkinson's. Additionally, insights from molecular modeling studies are discussed to elucidate the structural basis of interactions between these polyphenols and amyloid proteins, shedding light on their influence on aggregation pathways.

DOI: https://doi.org/10.1039/d5fo03331d
ACS Chem Neurosci. 2025 Oct 23.

Structure and Molecular Basis for Inhibiting Human SOD1 Aggregation by a Promising Decan Derivative Modulator: A Potential Therapeutic Strategy for Treating Amyotrophic Lateral Sclerosis (ALS).

Snehal Aouti, Padmini Kommu, Raghurama P Hegde, Asif Ali, Bharath Mm Srinivas, Sivaraman Padavattan, Balasundaram Padmanabhan.

  Misfolding and aggregation of the human superoxide dismutase (hSOD1) protein are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a motor neuron disease. The structural stabilization and enzymatic activation of hSOD1 occur upon binding to Cu/Zn ions and forming an intramolecular disulfide bond. Mutations in hSOD1 result in structural changes in the electrostatic and metal-binding loops, leading to the dissociation of Cu and/or Zn ions, which in turn triggers SOD1 oligomerization in ALS. Through X-ray studies, we have identified 1,2,10-decanetriol, a solubilizing agent commonly used in drug delivery, as a modulator that binds at the electrostatic loop and dimer interface regions of SOD1. The crystal structure of hSOD1 complexed with 1,2,10-decanetriol, refined to 1.97 Å resolution, reveals that the ligand stabilizes both loop regions as well as the dimeric structure of hSOD1. Notably, this compound exhibits a low nanomolar binding affinity of 32.40 ± 0.65 nM for hSOD1 and significantly inhibits aggregation in both metalated and demetalated wild-type and disease mutant proteins. Among the various inhibitors investigated for their ability to reduce SOD1 oligomerization, our study is the first to identify a molecule that binds at the electrostatic loop, as confirmed by in vitro experiments. These findings suggest that 1,2,10-decanetriol is a promising scaffold with potential inhibitory properties for library development against SOD1's amyloidogenic behavior.

Keywords:  1,2,10-decanetriol; X-ray structure; aggregation inhibition; amyotrophic lateral sclerosis; protein aggregation; superoxide dismutase 1

DOI:  https://doi.org/10.1021/acschemneuro.5c00168
Biochem Biophys Res Commun. 2025 Oct 15. pii: S0006-291X(25)01524-4. [Epub ahead of print]788 152808

On the potential roles of TDP-43 in the formation of membraneless organelles and their transformation into toxic aggregates.

Olga S Sergeeva, Margarita V Neklesova, Vladislav A Reushev, Alexey V Artemov, Irina M Kuznetsova, Konstantin K Turoverov, Vladimir N Uversky, Alexander V Fonin.

Trans-activation response (TAR) DNA-binding protein 43 (TDP-43) is an RNA-binding protein involved in the processing, transport, and regulation of mRNA translation. It is distributed in many tissues, including the brain, where it is found mainly in hippocampal neurons. Abnormal localization, hyperphosphorylation, and aggregation of TDP-43 are pathological signs of a group of neurodegenerative diseases known as TDP-43 proteinopathies. Despite the growing understanding of the physiological role of TDP-43 in ensuring neuronal plasticity and the formation of long-term memory, to date, there is no comprehensive data on the molecular and cellular mechanisms of the transformation of functional membraneless organelles (MLOs) containing TDP-43 into toxic aggregates and the pathogenesis of associated diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This review is devoted to highlighting the role of MLOs in the formation of irreversible aggregates, the role of TDP-43 in the formation of MLOs and their relationship with pathological forms of TDP-43, most often found in people suffering from neurodegenerative diseases.

DOI: https://doi.org/10.1016/j.bbrc.2025.152808
FASEB J. 2025 Oct 31. 39(20): e71160

Decoding Glycosylation in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Opportunities.

Haihan Yu, Xing Chen, Yang Yang, Mengke Gu, Kaidi Ren, Ziqing Wei.

  Glycosylation is a highly dynamic and complex post-translational modification that plays a pivotal role in regulating protein folding, trafficking, stability, and function. Accumulating evidence indicates that aberrant glycosylation is intimately involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This review provides a comprehensive overview of the molecular mechanisms by which the two predominant forms of glycosylation, N-glycosylation and O-GlcNAcylation, contribute to protein misfolding, synaptic dysfunction, neuroinflammation, and impaired stress responses in the diseased nervous system. We further explore the diagnostic potential of glycosylation biomarkers and emerging therapeutic strategies targeting glycosylation pathways. Special emphasis has been placed on recent advances in glycomic technologies, artificial intelligence-driven analytics, and nanocarrier-based drug delivery platforms. By integrating mechanistic insights with translational applications, this review highlights glycosylation as both a pathological driver and a promising therapeutic target in neurodegenerative disorders.

Keywords:  glycosylation; neurodegenerative diseases; neuroinflammation; post‐translational modification; therapeutic strategies

DOI:  https://doi.org/10.1096/fj.202502809R
Curr Drug Targets. 2025 Oct 21.

Rationally Engineered Small Molecules: Pharmacophore Modeling and Molecular Docking Studies Targeting Toxic Polyglutamine (PolyQ) Repeats in Huntington's Disease.

Jangampalli Adi Pradeepkiran, Amardev Rajesh Vatapatri, Philip Irwin Motakatla, Bhragavi Pasupuleti, Manne Munikumar.

   INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by the accumulation of mutant huntingtin protein (mHTT) with expanded polyglutamine (polyQ) tracts. These aggregates contribute to neuronal toxicity and disease progression. Targeting aggregation, especially at the N-terminal domain (N17), may offer a therapeutic strategy. This study aims to identify potential small-molecule inhibitors that can bind to aggregation-prone regions of mHTT using computational methods.
METHODS: We characterized polyQ repeat regions and the N17 domain using CASTp to identify active sites. Pharmacophore models were generated using LigandScout based on the glutamate inhibitor 6-Diazo-5-oxo-L-norleucine (DON). Structurally similar ligands were screened from PubChem. Ten candidates were selected and evaluated through molecular docking. ADME/Toxicity and drug-likeness analyses were performed to assess pharmacokinetic suitability.
RESULTS: Ten DON-like ligands showed favorable pharmacophore features. Docking studies identified five compounds with strong binding affinities and key interactions with the polyQ region. These top candidates also demonstrated acceptable ADME/T profiles and drug-likeness.
DISCUSSION: The five lead compounds identified in this study demonstrate potential to interfere with mHTT aggregation, a key pathological feature of HD. Their favorable binding and pharmacokinetic properties support their candidacy for further development. However, in silico predictions require experimental validation. Future in vitro and in vivo studies are essential to confirm their efficacy and safety.
CONCLUSION: This study presents five promising small-molecule inhibitors for HD, laying the groundwork for future therapeutic development targeting mHTT aggregation.

Keywords:  Huntington's disease; ligands; molecular docking studies.; mutant huntingtin; pharmacophore; polyglutamine

DOI:  https://doi.org/10.2174/0113894501393938251006195954
J Inorg Biochem. 2025 Oct 14. pii: S0162-0134(25)00293-4. [Epub ahead of print]275 113112

Metal ions control amyloid catalysis.

Fiamma Ayelen Buratti, Ranjeet Kumar, Pernilla Wittung-Stafshede.

  Pathological amyloids, such as those formed by the protein α-synuclein in Parkinson's disease, have recently been shown to catalyze hydrolysis of ester and phosphoester bonds in vitro. Here, we report that this activity is modulated by divalent metal ions copper (Cu(II)) and zinc (Zn(II)). Specifically, α-synuclein amyloids formed in the presence of Zn(II) are catalytically inactive towards dephosphorylation of adenosine triphosphate (ATP) and cannot bind a fluorescent analog of ATP. In contrast, amyloids formed in the presence of Cu(II) retain catalytic activity towards ATP that is comparable to that of amyloids formed without metal ions. Amyloids of the α-synuclein variant with histidine at position 50 replaced by alanine (H50A) are inactive in catalyzing ATP hydrolysis independent of Zn(II); however, when these amyloids are formed in the presence of Cu(II), catalytic activity and ATP binding is restored. For lipase activity on a model substrate, both wild-type and H50A α-synuclein amyloids are catalytically active regardless of Cu(II), whereas amyloids of both variants formed in the presence of Zn(II) exhibit no such activity. In sharp contrast, hydrolysis of para-nitrophenyl acetate (pNPA) is insensitive to both metal ions and H50A mutation in the amyloids. Given the common occurrence of metal ion dysregulation in neurodegenerative disorders, and the propensity of many amyloidogenic proteins to bind metal ions, our findings imply that amyloid catalytic activity may be modulated by metal ions in vivo.

Keywords:  Amyloid; Catalytic activity; Hydrolysis; Metal ions; Parkinson; α-synuclein

DOI:  https://doi.org/10.1016/j.jinorgbio.2025.113112
Curr Protein Pept Sci. 2025 Oct 21.

Therapeutic Horizons for Parkinson's Disease: Current Relevance of PNA5 in Memory and Cognition.

Kousik Maparu, Dhrita Chatterjee, Nileshwar Kalia, Romanpreet Kaur, Shamsher Singh.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized primarily by the progressive loss of dopaminergic neurons in the substantia nigra and the pathological aggregation of α-synuclein. While some genetic and environmental factors contribute to the development of PD, emerging evidence suggests that specific proteins and molecules may have the potential to slow down, reverse, or mitigate the progression of the disease. Recently, the neuroprotective potential of peptide nucleic acid 5 (PNA5) has garnered attention for its ability to restore cognitive functions in PD. PNA5 is an angiotensin (1-7) agonist peptide molecule that targets α-synuclein mRNA to inhibit its translation and aggregation. Key areas explored include the role of PNA5 in reducing toxic α-synuclein oligomers and fibrils, modulating neuroinflammation, preserving mitochondrial function, and harnessing molecular chaperones and angiotensin-MAS receptor signalling pathways for cellular homeostasis. This review emphasizes the significance of PNA5 in addressing the unmet needs of PD treatment, particularly in the areas of memory and cognition. By targeting the molecular basis of cognitive decline, PNA5 represents a transformative candidate for disease-modifying therapy that could revolutionize approaches to treating neurodegenerative disorders. Future studies should concentrate on establishing delivery methods, evaluating long-term efficacy, and addressing safety concerns.

Keywords:  MAS receptor; PNA5; Parkinson’s disease; angiotensin; cognitive impairment.; neuroinflammation

DOI:  https://doi.org/10.2174/0113892037389890250925014102