bims-proned 2025-11-16 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–11–16
eighteen papers selected by
Verena Kohler, Umeå University

Current Understanding of Protein Aggregation in Neurodegenerative Diseases.
Inhibition of α-synuclein aggregation by hesperidin as a potent anti-amyloidogenic polyphenol: A computational approach and MM-PBSA /ADMET analysis.
Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.
Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study.
Ambroxol displaces α-synuclein from the membrane and inhibits the formation of early protein-lipid coaggregates.
Anle138b mitigates post-hypoxic cognitive impairment, α-Synuclein aggregation and UPR activation in Drosophila melanogaster.
Targeting endoplasmic reticulum stress and protein misfolding in schizophrenia: the emerging promise of sigma-1 receptor agonists.
Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.
Conformational constraints and ligand interactions are key determinants of the distinct aggregation pathways observed in human serum albumin.
Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.
Advances in Probing Amyloid Heterogeneity Using Vibrational Spectroscopy and Imaging.
The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.
Inhibition of PDE4 Alleviates Endoplasmic Reticulum Stress and Neuronal Damage via Activation of Nrf2/HO-1 in Parkinson's Disease.
Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis.
Targeting the alpha-synuclein protein to treat Parkinson's disease using novel inhibitors identified using an integrated computational drug development approaches.
Nanoenabled Sequestration of Redox Copper Modulates Lysozyme Aggregation and Maintains Lipid Homeostasis to Alleviate Mitochondrial Health.
Silymarin-Based Nanosheets Efficiently Protect Mitochondria against Oxidative Damage Mediated by α-Synuclein Amyloid Aggregates.
Development of a targeted BioPROTAC degrader selective for misfolded SOD1.

Int J Mol Sci. 2025 Oct 30. pii: 10568. [Epub ahead of print]26(21):

Current Understanding of Protein Aggregation in Neurodegenerative Diseases.

Chen Hu, Menghan Lin, Chuangui Wang, Shengping Zhang.

  Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.

Keywords:  aggregate clearance; neurodegenerative diseases; oligomers; protein aggregates; therapeutic strategies

DOI:  https://doi.org/10.3390/ijms262110568
Biochem Biophys Rep. 2025 Dec;44 102318

Inhibition of α-synuclein aggregation by hesperidin as a potent anti-amyloidogenic polyphenol: A computational approach and MM-PBSA /ADMET analysis.

Zainab Abdullah Waheed, Haider Khabt Aboud, Jasem Hanoon Hashim Al-Awadi, Azhaar Mousa Jaffar Al-Mousawy, Khudhair Rashid Khudhair Alzubaidi.

  A significant part of amyloidogenic illnesses is played by protein misfolding and aggregation caused by intrinsically disordered protein (IDP) self-assembly in Parkinson's disease (PD). In PD, cytotoxic amyloid aggregates of aberrant alpha-synuclein (α-syn) are formed in motor neurons, causing neurodegeneration. Beta-sheet-rich amyloid aggregates are a promising target for mitigating their neurodegenerative consequences. A significant amount of work has been invested in developing chemical compounds that either prevent aggregates from forming or facilitate their breakdown. Finding them might provide a workable strategy for creating a powerful remedy. Several studies indicate that neurological disorders can be treated using small-molecule inhibitors derived from polyphenolic flavonoid compounds. We have thus identified a potential flavonoid molecule that can effectively inhibit the amyloidogenic activity of α-syn through molecular docking and molecular dynamics (MD) simulations. Hesperidin, Morin, and Myricetin were shown to be potential therapeutic leads in the initial screening of flavonoids. Compared to other compounds, the hesperidin-α-Syn combination showed a larger residual energy contribution (ΔE binding -92.69 ± 0.31 kJ mol-1) and significant binding (6.58 kcal/mol). Secondary structural analysis showed an increased tendency for β-sheets (35 %), with the percentage of β-sheets decreasing in the presence of Hesperidin (29 %). The results showed that Hesperidin binding resulted in a significant reduction in hydrogen bonding between α-syn peptide chains compared to unbound protein. The findings demonstrated that, in contrast to other compounds, Hesperidin alters protein flexibility, hydrophobicity, and structural stability. Therefore, Hesperidin may be a promising treatment option to reduce the negative consequences of PD by efficiently mitigating α-syn amyloid-induced neurotoxicity.

Keywords:  Aggregation; Flavonoid compounds; Hesperidin; MD simulation; Parkinson's disease; α-Syn

DOI:  https://doi.org/10.1016/j.bbrep.2025.102318
Cells. 2025 Oct 28. pii: 1686. [Epub ahead of print]14(21):

Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.

Satomi Nadanaka, Yuto Imamoto, Toru Takarada, Masafumi Tanaka, Hiroshi Kitagawa.

  Chondroitin sulfate (CS) chains on the cell surface are sulfated in various patterns, and this structure is the basis of CS function. We aimed to investigate the role of chondroitin 4-O-sulfotransferase-1 (C4ST-1), the enzyme responsible for the 4-sulfation of CS, in redox homeostasis and protein aggregation in mouse neuroblastoma Neuro2a and neural progenitor C17.2 cells. Results showed that C4ST-1 deficiency significantly reduced 4-sulfated CS, which led to markedly decreased intracellular glutathione levels and increased reactive oxygen species production. Mechanistically, C4ST-1 loss reduced the CS modification of neurocan, decreased the stability of the cystine transporter xCT, and decreased intracellular glutathione levels. This redox imbalance promoted protein aggregation and caused lysosomal membrane damage, indicating a failure of protein quality control. Although C4ST-1 deficiency alone did not cause tau protein aggregation, it significantly accelerated the aggregation of a familial tauopathy mutant following the introduction of seeds. These findings suggest that C4ST-1-mediated CS sulfation regulates the intracellular redox state and tau pathology. Thus, C4ST-1 may serve as a therapeutic target for neurodegenerative diseases.

Keywords:  chondroitin sulfate; glutathione; oxidative stress; proteoglycan; tau aggregation

DOI:  https://doi.org/10.3390/cells14211686
RSC Med Chem. 2025 Oct 22.

Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study.

Zuzana Smahelova, Lucie Svobodova, Jindrich Sedlacek, Michael Adamek, Marketa Pimkova Polidarova, Pavel Majer, Ales Machara, Klara Grantz Saskova.

Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutant proteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases and is often associated with impaired protein clearance mechanisms. The transcription factor nuclear factor erythroid 2-related factor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasome synthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeutic strategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identified bis(phenylmethylene)cycloalkanone derivatives as NFE2L1 activators capable of inducing proteasome subunit expression, increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed a new library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examining how specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure-activity relationships within this pathway.

DOI: https://doi.org/10.1039/d5md00584a
Chem Sci. 2025 Oct 31.

Ambroxol displaces α-synuclein from the membrane and inhibits the formation of early protein-lipid coaggregates.

Jesper E Dreier, Alisdair Stevenson, Elliot Carles, Katharina Schott, Thomas C T Michaels, Céline Galvagnion.

Parkinson's disease (PD) is a neurological disorder characterized by neuronal loss and the deposition of α-synuclein-lipid coaggregates in the brain of patients as well as disruptions in lipid metabolism. Mutations in the gene GBA, which encodes the lysosomal glycoprotein Glucocerebrosidase, are together the most important genetic risk factor for PD and have been associated with lysosomal dysfunction, accumulation of pathological α-synuclein as well as major changes in both the levels and properties of lipids. Ambroxol, a small molecule chaperone capable of binding and stabilizing Glucocerebrosidase, was found to revert changes in lipid levels and increase in α-synuclein levels due to GBA mutations potentially via restoring lysosomal function. Here, we show that Ambroxol also has a direct effect on α-synuclein-lipid coaggregation by inhibiting the primary nucleation step in the aggregation process. We find that Ambroxol not only displaces α-synuclein from negatively charged membranes but also prevents the formation of early α-synuclein-lipid coaggregates during primary nucleation. These results suggest that Ambroxol may have beneficial effects on other synucleinopathies, such as multiple system atrophy and dementia with Lewy Bodies, that are also characterised by the aggregation of α-synuclein into amyloid fibrils.

DOI: https://doi.org/10.1039/d5sc06116d
Acta Neuropathol Commun. 2025 Nov 11. 13(1): 230

Anle138b mitigates post-hypoxic cognitive impairment, α-Synuclein aggregation and UPR activation in Drosophila melanogaster.

Aaron T Fehr, Jennifer Jung, Alma Kokott-Vuong, Sabri E M Sahnoun, Aya A Ezzat, Michael Huber, Tonya M Bliss, Aaron Voigt, Jörg B Schulz, Pardes Habib.

  Cerebral ischemia increases the risk of post-stroke cognitive impairment (PSCI), but the underlying molecular mechanisms remain unclear. Emerging evidence suggests that hypoxia/ischemia-induced oxidative and endoplasmic reticulum (ER) stress may contribute to protein misfolding and α-Synuclein (α-Syn) aggregation, potentially triggering the unfolded protein response (UPR) to alleviate ER stress. Using bimolecular fluorescence complementation in Drosophila melanogaster and HEK-293 cells, we investigated the effect of acute, repetitive and chronic hypoxia on α-Syn aggregation, UPR activation, mortality, longevity, locomotor function, sleep, and cognition. Furthermore, we evaluated the post-hypoxic in vivo biodistribution and therapeutic efficacy of the aggregation inhibitor anle138b. Acute severe hypoxia induced more α-Syn aggregation than chronic or repetitive hypoxia, resulting in higher mortality, reduced longevity, delayed motor recovery, cognitive impairment, and activation of the detrimental PERK branch of the UPR. Anle138b significantly reduced α-Syn aggregation, repressing post-hypoxic PERK activation and improving survival and decision-making. Our findings demonstrate the effectiveness of anle138b in mitigating hypoxia-induced α-Syn aggregation and cognitive impairment, paving the way for future studies on its potential as a therapeutic strategy for PSCI.

Keywords:  ER stress; Hypoxia; Neurodegeneration; Neuroprotective therapy; Post-stroke cognitive impairment; Stroke

DOI:  https://doi.org/10.1186/s40478-025-02099-5
Psychopharmacology (Berl). 2025 Nov 11.

Targeting endoplasmic reticulum stress and protein misfolding in schizophrenia: the emerging promise of sigma-1 receptor agonists.

Mariam K Ahmed, Kareem Abdou, Weam W Ibrahim, Ahmed F Mohamed, Noha A El-Boghdady.

  Schizophrenia is a severe psychiatric disorder marked by significant cognitive, perceptual, and social deficits, the neurobiological basis of which remains incompletely elucidated. Increasing evidence implicates disruptions in protein homeostasis, including misfolding and aggregation of key neuronal proteins, as contributing factors to its pathogenesis. While proteinopathies have been extensively studied in neurodegenerative diseases, their role in schizophrenia has only recently gained attention. Central to these processes is endoplasmic reticulum (ER) stress and the activation of the unfolded protein response, which regulate protein folding and cellular quality control. Dysregulation of ER stress pathways, alongside impaired chaperone protein function and mitochondrial dysfunction, can lead to accumulation of misfolded proteins and neuronal dysfunction. Proteins such as DISC1, CRMP1, NOS1AP, and others have been identified with altered expression and aggregation patterns in schizophrenia, linking protein abnormalities to disease pathology. Additionally, mounting evidence suggests that chronic ER stress can activate microglia, the brain's immune cells, triggering the release of proinflammatory cytokines and promoting neuroinflammation. Sigma-1 receptor, a unique ER chaperone protein involved in modulating ER stress and calcium signaling, has emerged as a critical regulator of neuronal proteostasis and survival. Agonists of the sigma-1 receptor show promising therapeutic potential by alleviating ER stress, enhancing neuroprotection, halting inflammation, and restoring cellular homeostasis in preclinical models of schizophrenia and other brain disorders. In this review, we will discuss these interconnected molecular mechanisms, highlighting novel therapeutic pathways focused on proteostasis restoration and sigma-1 receptor modulation, which offer a promising avenue for future interventions in schizophrenia.

Keywords:  Endoplasmic reticulum stress; Protein misfolding; Schizophrenia; Sigma-1 receptor; Unfolded protein response

DOI:  https://doi.org/10.1007/s00213-025-06940-6
Sci Rep. 2025 Nov 13. 15(1): 39867

Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.

Veronika Kovač, Veronika Huntosova, Viktoria Fedorova, Nikitas Georgiou, Jian-Zong Lai, Fan-Ching Chien, Shean-Jen Chen, Filip Dolenec, Katarina Siposova.

  Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.

Keywords:  Amyloid aggregation; Ferrocenyl-pyrazole/pyrimidine-curcumin derivatives; Glioblastoma

DOI:  https://doi.org/10.1038/s41598-025-23467-0
Int J Biol Macromol. 2025 Nov 10. pii: S0141-8130(25)09509-1. [Epub ahead of print] 148952

Conformational constraints and ligand interactions are key determinants of the distinct aggregation pathways observed in human serum albumin.

Chanchal Chauhan, Kehkashan Naaz, Shivani A Muthu, Suhel Parvez, Basir Ahmad.

  Protein aggregation is a fundamental phenomenon linked to many amyloid-associated disorders, production of therapeutic proteins and biomaterial. Human serum albumin (HSA), a multidomain protein, exhibits diverse aggregation behaviors under physiological stress. Here, we investigated how domain-specific ligands (DSLs) such as hemin for domain-I, bilirubin for domain-II, and diazepam for domain-III influences HSA aggregation reactions. Using biophysical techniques including circular dichroism, intrinsic fluorescence, thermal unfolding, quenching assays, red edge excitation shift (REES) analysis, transmission electron microscopy, FTIR, and molecular dynamic simulation (MD-simulation), we show that effect of ligand binding induces distinct aggregation morphologies. Native HSA forms β-sheet-rich worm-like fibrils at ~65 °C and pH 7.4. Hemin binding accelerated aggregation by ~2.5-fold and promoted spherical oligomers, whereas bilirubin slowed it by 2-fold leading to amorphous aggregates, and diazepam produced fibrils similar to native HSA. Ligand binding reduced conformational dynamics and altered equilibrium states, with hemin and bilirubin inducing compactness and internalization of tryptophan residues, thereby decreasing fibril elongation tendency. These findings highlight the role of effect of domain-specific in redesigning aggregation precursor states and pathways. Our study provides mechanistic insights into how small molecules modulate the aggregation landscape of multidomain proteins. By showing that ligands can redirect aggregation toward distinct off-pathway species, this work elucidates the mechanistic basis by which ligand binding modulates protein assembly pathways and aggregates morphology.

Keywords:  Aggregation kinetics; Amyloid aggregation; Domain-specific ligands; Protein misfolding; Serum albumin; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148952
Hum Mol Genet. 2025 Nov 13. pii: ddaf166. [Epub ahead of print]

Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.

Manoj Kumar, Ricardo A Feldman.

  Bi-allelic mutations in GBA1, a gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase), cause Gaucher disease (GD). Although GD carriers do not exhibit clinical manifestations, GBA1 mutations are the highest risk factor for Parkinson's disease (PD) in GD patients and carriers of the disease [1-5]. GCase breaks down glucosylceramide (GluCer), a sphingolipid that accumulates in GD. GluCer is deacylated by the lysosomal enzyme acid ceramidase (ACDase) to glucosylsphingosine (GluSph) [6-8]. GluSph is neurotoxic and accumulates to high levels in neuronopathic GD brains [9, 10]. However, whether this metabolic pathway involving ACDase plays a role in GBA1-associated PD (GBA1/PD) is not known. In this report we used induced pluripotent stem cells (hiPSCs) from PD patients harboring heterozygote GBA1 mutations to examine the role of ACDase in promoting α-synuclein accumulation and aggregation, a hallmark of PD. Compared to isogenic controls, hiPSC-derived PD dopamine (DA) neurons had elevated levels of pathogenic α-synuclein species. There was also reduced nuclear localization of transcription factor EB (TFEB), impaired autophagy, and decreased levels of cathepsin D (CathD), a lysosomal protease involved in α-synuclein degradation [11]. Treatment of the mutant DA neurons with a number of different ACDase inhibitors, or CRISPR/Cas9 knockdown (KD) of the ASAH1 gene, reversed all the phenotypic abnormalities of the mutant DA neurons. We conclude that in GBA1/PD-DA neurons, ACDase contributes to deregulation of key nodes of the autophagy/lysosomal pathway (ALP) involved in α-synuclein clearance. Our results suggest that ACDase is a potential therapeutic target for treating GBA1-associated PD.

Keywords:  GBA1; Parkinson’s disease; TFEB; acid ceramidase; ASAH1; α-synuclein

DOI:  https://doi.org/10.1093/hmg/ddaf166
J Phys Chem B. 2025 Nov 14.

Advances in Probing Amyloid Heterogeneity Using Vibrational Spectroscopy and Imaging.

Cade K Rohler, Kayla A Hess, Lauren E Buchanan.

The misfolding and aggregation of proteins into amyloid fibrils are associated with numerous human diseases; however, our understanding of the mechanisms by which amyloid proteins exert their toxicity remains limited. This gap in knowledge can largely be attributed to the significant polymorphism of species that form during aggregation, ranging from short-lived soluble oligomers to various polymorphic fibrils, compounded by the complex interplay of other proteins and biomolecules. Vibrational spectroscopies are particularly well-suited for studying these heterogeneous mixtures and, with the integration of site-specific probes, can provide residue-level structural information. This perspective highlights recent advances in the application of Raman and infrared (IR) spectroscopy and imaging techniques to elucidate aggregation mechanisms, characterize oligomer and fibril structures, analyze plaque compositions, and investigate the effects of coassembly and cross-seeding. These efforts move us toward a greater understanding of how amyloids form under disease-relevant conditions, which may provide new routes toward targeted therapeutics.

DOI: https://doi.org/10.1021/acs.jpcb.5c06431
Acta Neuropathol. 2025 Nov 11. 150(1): 51

The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.

George Tsafaras, Diego Cabezudo, Lot Wetzels, Iraklis Tsakogias, Ajantha Abey, Eduard Bentea, Maria Sanchiz-Calvo, Chris Van den Haute, Richard Wade-Martins, Veerle Baekelandt.

  Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including tau, are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy but may involve multiple, coexisting proteinopathies. Mutations in LRRK2, particularly the G2019S (GS), are the most common cause of familial PD. LRRK2-PD has been associated with both αSyn and tau pathology; however the mechanistic links between LRRK2 dysfunction and protein aggregation remain incompletely defined. Here we opted to investigate whether LRRK2 contributes to αSyn and tau pathology through common molecular pathways or via distinct cellular mechanisms. Viral vector-mediated αSyn overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration, increased phosphorylated αSyn levels, pronounced neuroinflammation, and accumulation of lysosomal proteins, suggesting impaired αSyn clearance and immune activation as key drivers. Human iPSC-derived dopaminergic neurons from GS LRRK2 PD patients mirrored these findings. In contrast viral vector-mediated overexpression of tau in GS LRRK2 knock-in mice promoted tau phosphorylation but did not significantly affect neuroinflammation, lysosomal markers, or neurodegeneration, indicating a primarily cell-autonomous mechanism. Our results reveal a mechanistic divergence in how GS LRRK2 impacts αSyn and tau pathologies, supporting the notion that LRRK2 kinase activity contributes to PD pathogenesis through different pathways, thereby highlighting its potential as a therapeutic target in both familial and sporadic PD.

Keywords:  Alpha-synuclein; LRRK2; Parkinson’s disease; Tau

DOI:  https://doi.org/10.1007/s00401-025-02956-6
Mol Neurobiol. 2025 Nov 15. 63(1): 49

Inhibition of PDE4 Alleviates Endoplasmic Reticulum Stress and Neuronal Damage via Activation of Nrf2/HO-1 in Parkinson's Disease.

Jiahong Zhong, Yunyun Qin, Junling Xue, Qiuming Wang, Xiaochun Lin, Guozhu Tan, Huilin Xiao, Xihui Yu, Zhuomiao Lin.

  Parkinson's disease (PD) is a typical neurodegenerative disorder characterized by the aggregation of pathological α-synuclein. The accumulation of misfolded proteins can induce severe endoplasmic reticulum stress (ERS) and lead to neuronal damage. In this study, we investigated the effects of phosphodiesterase 4 (PDE4) inhibitors on ER homeostasis in a PD model. In vitro experiments using SH-SY5Y cells demonstrated that treatment with 1-methyl-4-phenylpyridinium ion (MPP+) effectively induced ERS and cellular damage. In contrast, PDE4 inhibition significantly reduced the expression of key ERS markers, including G protein-coupled receptor 78 (GPR78) and C/EBP homologous protein (CHOP), and promoted cell survival. Mechanistically, PDE4 inhibition facilitated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), leading to the upregulation of heme oxygenase-1 (HO-1) and activation of the antioxidant pathway, which effectively alleviated MPP+-induced ERS and neuronal damage. In a mouse PD model, administration of the PDE4 inhibitor roflupram (ROF) significantly activated the antioxidant pathway. This was accompanied by improved motor coordination, demonstrating the neuroprotective effects of ROF. These findings suggest that PDE4 inhibition may represent a promising therapeutic strategy for PD.

Keywords:  Endoplasmic reticulum stress; MPP+ ; Nrf2/HO-1; PDE4; Parkinson's disease

DOI:  https://doi.org/10.1007/s12035-025-05345-y
Bioorg Chem. 2025 Nov 02. pii: S0045-2068(25)01070-3. [Epub ahead of print]167 109190

Modifications of NU-9, a potent protein aggregation inhibitor. Properties and activity in a cellular model of amyotrophic lateral sclerosis.

Mohamed F Elmansy, Pedro Soares, Jose Ricardo D Dos Remedios, Raghad Nowar, Susan G Fox, Anan Yu, William L Klein, Richard I Morimoto, Richard B Silverman.

  Amyotrophic lateral sclerosis (ALS) is a fast-progressing disease characterized by the loss of voluntary movements and death due to respiratory failure. The presence of protein aggregates is a major hallmark of the disease. Hence, targeting the pathological protein aggregation may provide more efficient therapeutics for ALS. Recently, we reported a cyclohexane-1,3-dione (NU-9) with in vitro anti-aggregation capacity and promising in vivo efficacy in ALS animal models, which validated our approach toward the development of novel and potentially more effective ALS therapeutics. Herein, we report the design and synthesis of a new series of small-molecule derivatives of NU-9 and the evaluation of their in vitro anti-aggregation activity in a PC12 cellular model containing an SOD1G85R familial ALS mutation. The most promising compound (20) presented an in vitro anti-aggregation potency comparable to that of NU-9. Moreover, the better in vitro BBB permeability, microsomal stability, and toxicity profile of 20 also suggests a potentially higher efficacy in vivo.

Keywords:  Amyotrophic lateral sclerosis; Cyclohexane-1,3-diones; Protein aggregation; SOD-1; Small-molecules

DOI:  https://doi.org/10.1016/j.bioorg.2025.109190
In Silico Pharmacol. 2025 ;13(3): 168

Targeting the alpha-synuclein protein to treat Parkinson's disease using novel inhibitors identified using an integrated computational drug development approaches.

Arif Jamal Siddiqui, Sadaf Jahan, Juhi Saxena, Manojkumar Sachidanandan, Riadh Badraoui, Mohd Adnan.

  Alpha-synuclein (α-syn) is a 140 amino acid neuronal protein linked to different neurodegenerative disorders. A point mutation in its gene has been related to a rare family type of Parkinson's disease (PD), and more alterations have been discovered in familial PD cases. Abnormal processing of α-syn can cause pathological alterations, altering its binding characteristics and functionality. Clinical trials aimed at reducing α-syn aggregation have faced obstacles due to challenges in identifying effective drugs during preclinical studies. Method To address this issue, we present computational methods that combines pharmacophore modeling, molecular docking, molecular dynamics, free energy calculations, and similarity index investigations to find possible hit compounds for preventing α-syn aggregation. Results A validated pharmacophore model was used to screen the ZINC natural product library, followed by established computational pipeline, yielding four novel inhibitors (ZINC000150351590, ZINC000299817386, ZINC000085509805, ZINC000095911811) with strong binding affinities (- 9.43 to - 9.06 kcal/mol). Molecular dynamics simulations confirmed stable protein-ligand complexes (average RMSD < 2.5 Å), while MM/PBSA analysis showed favorable binding free energies (- 56.7 to - 49.2 kcal/mol). Conclusion Evaluation of docking performance, stability, and binding energetics using MM/PBSA enabled the identification of four natural inhibitors of α-syn aggregation. These compounds represent promising leads for further investigation in Parkinson's disease drug discovery.

Keywords:  Alpha-synuclein; Computational biology; Free energy calculation; Molecular dynamics; Parkinson's disease; Pharmacophore modelling

DOI:  https://doi.org/10.1007/s40203-025-00477-4
Small. 2025 Nov 11. e08683

Nanoenabled Sequestration of Redox Copper Modulates Lysozyme Aggregation and Maintains Lipid Homeostasis to Alleviate Mitochondrial Health.

Manik Bathla, Trilok Chand Saini, Nandini Teji, Shiwani Randhawa, Rahul Bhardwaj, Amitabha Acharya.

  Abnormalamyloid deposition is a prominent hallmark of several neurodegenerative diseases (NDs), however, therapies involving direct amyloid degradation haveresulted limited success, underscoring the need for refined intervention strategies and alternative therapeutic targets. Emerging evidence implicates dysregulated lipid metabolism, particularly aberrant lipid droplet (LD)accumulation, as a key contributor to ND pathology. Notably, intracellularlipid homeostasis is tightly regulated by copper (Cu) levels, and elevated Cuconcentrations have also been detected in amyloid aggregates in ND brains, suggesting mechanistic link between metal dyshomeostasis, amyloid aggregation, and lipid dysregulation. To address this, we developed chemically modifiedplant-based fluorescent carbon dots (PEI@HCDPEG, ∼12 nm) withspecific Cu-chelating ability. PEI@HCDPEG effectively mitigatedCu-induced protein aggregation (∼2.8 fold reduction) and significantly decreased intracellular LD accumulation (∼1.25 fold) by inhibiting lipid peroxidation and modulating lipid metabolic pathways. Lipidomic analysis revealed that PEI@HCDPEG pretreatment led to reduced levels ofneutral lipids, including cholesteryl esters (∼1.5 fold) and triglycerides(∼1.2 fold). Furthermore, PEI@HCDPEG decreased LD diameter from ∼7µmto ∼3µm, indicating restored lipid homeostasis. Consistent results were also observedin C. elegans studies. These multi-dentate, metal ion chelator nanoparticles hold promise as novel therapeutic agents for NDs.

Keywords:  amyloids; charged nanoparticles; copper ion sequestration; human lysozyme; lipid droplets; lipid homeostasis; neurodegenerative disease

DOI:  https://doi.org/10.1002/smll.202508683
ACS Chem Neurosci. 2025 Nov 11.

Silymarin-Based Nanosheets Efficiently Protect Mitochondria against Oxidative Damage Mediated by α-Synuclein Amyloid Aggregates.

Zahra Mahmoudi Eshkaftaki, Saeed Emadi, Ali Akbar Meratan.

  An increasing body of evidence suggests that mitochondrial dysfunction mediated by α-synuclein (α-syn) aggregates plays a key role in the pathogenesis of Parkinson's disease (PD), leading to intensive research for the discovery and development of compounds with mitoprotective effects. Silymarin (SIL) is a complex mixture of flavonolignans with a wide range of protective effects on mitochondria under stress conditions. Herein, the potency of SIL, in bulk and nano forms, in protecting mitochondria against oxidative damage induced by α-syn aggregates has been investigated. Mitochondria were isolated from rat brain and liver tissues as well as human neuroblastoma SH-SY5Y cells, and damage was evaluated by using a range of biochemical assays. The obtained results show a substantial difference in the response of various mitochondria to oxidative damage induced by α-syn aggregates, with brain mitochondria exhibiting the highest vulnerability. We found that incubation of mitochondria with either bulk or nano forms of SIL before exposure to α-syn aggregates significantly attenuated oxidative damage in a dose-dependent manner. In parallel, α-syn aggregates aged in the presence of bulk or nano forms of SIL considerably lost their capacity to cause mitochondrial damage. While both bulk and nano forms of SIL showed significant mitoprotective effects, SIL nanosheets were much more effective. Possible mechanisms relating to the mitoprotective effects of SIL and the higher efficacy of SIL nanosheets are discussed. The obtained results suggest natural polyphenol-based nanoparticles as an efficient therapeutic approach in relation to amyloid-related diseases, such as PD.

Keywords:  amyloid; mitochondria; nanonization; oxidative damage; silymarin; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.5c00793
Nat Commun. 2025 Nov 10. 16(1): 9713

Development of a targeted BioPROTAC degrader selective for misfolded SOD1.

Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke McAlary, Jeremy S Lum, Justin J Yerbury.

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1G93A mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-025-65481-w