Search Results (486)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

Tau protein misfolding and aggregation are central to Tauopathies, yet the temporal dynamics of Tau interactions in vivo remain poorly understood. Here, we applied quantitative proteomics to demonstrate that the interactome of human Tau in adult Drosophila brains changes dynamically over a 12-day time course, revealing a progressive shift from early cytosolic and ribosomal associations to late enrichment of mitochondrial and synaptic partners. Notably, the mitochondrial pore protein Porin/VDAC1 was identified as a late-stage interactor and functional analyses demonstrated that Tau overexpression impairs mitochondrial respiration, elevates oxidative damage, and disrupts carbohydrate homeostasis. To validate this temporally specific interaction, Porin was downregulated, resulting in reduced Tau mitochondrial association, phosphorylation and aggregation. Paradoxically, however, Porin attenuation exacerbated Tau-induced toxicity, including shortened lifespan, locomotor deficits, and impaired learning. These findings indicate that while Porin facilitates pathological Tau modifications, it is also essential for neuronal resilience, highlighting a complex role in modulating Tau toxicity. Our study provides a temporal map of Tau-associated proteome changes in vivo and identifies mitochondria as critical mediators of Tau-driven neurodegeneration. Full article

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are characterized by progressive neuronal loss, driven mainly by the misfolding, aggregation, and accumulation of each disease’s specific proteins. These pathogenic aggregates, including tau, α-synuclein, TDP-43, and huntingtin, disrupt cellular proteostasis and initiate cascades of neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic failure. While protein aggregation has been a long-recognized hallmark of these disorders, growing evidence points towards a more complex interplay of initial molecular pathways with defects in RNA processing, stress granule pathology, and cell-type-specific vulnerability. Notably, such events may manifest differentially with respect to sex and are further modulated by age-related loss of the protein quality control processes like the ubiquitin–proteasome pathway, autophagy–lysosome pathway, and molecular chaperones. This review synthesizes current insights into the structural and functional dynamics of protein aggregation and its significance for neuronal well-being. It highlights the role of post-translational modifications, prion-like transmission, and aggregation kinetics in the regulation of toxicity. The review further discusses promising therapeutic strategies centered on restoring proteostasis, including small molecules that inhibit aggregation, protein clearance pathway enhancers, immunotherapy, antioxidant therapy, and diagnostic prospects such as the identification of reliable molecular signatures in bodily fluids that can reflect pathological changes even before clinical symptoms emerge. Advancements in single-cell transcriptomics and multi-omics platforms, which are changing our understanding of disease onset and progression and opening avenues for precision medicine and personalized treatments, were also discussed. Ultimately, deciphering the molecular logic that distinguishes physiological from pathological protein assemblies and understanding how cellular systems fail to adapt under stress will be key to the development of effective, disease-modifying therapies for these debilitating disorders. Full article

Metals are essential for the physiological and biochemical processes in the human brain. However, their accumulation can cause neurotoxic effects, including the generation of reactive oxygen species and structural changes in biomolecules. This study aimed to assess the presence and distribution of metals in the human globus pallidus internus using Particle-Induced X-ray Emission (PIXE) and Scanning Electron Microscopy with Energy-Dispersive X-ray (SEM-EDX). Post-mortem brain tissue samples from six individuals without clinical neuropathological findings were analysed. PIXE analysis revealed the presence of Fe, Cr, Al, Zn, Pb, and Ca. SEM-EDX analysis provided the qualitative elemental composition of an observed aggregate, revealing C, N, O, Na, Ca, Al, Si, S, K, Mg, Cl, Fe, Ni, and Cr. Our findings suggest that metal accumulation in the brain can result from environmental pollution and protein aggregation, as well as biomineralisation processes that sequester metal ions to mitigate their harmful effects. A deeper understanding of these accumulation pathways could contribute to improved therapeutic strategies for neurological diseases associated with metal toxicity. Full article

Catalase, a pivotal antioxidant enzyme, plays a central role in converting hydrogen peroxide (H₂O₂) into oxygen and water, thereby safeguarding cells from oxidative damage. In patients with diabetes, obesity, Alzheimer’s disease (AD), and Parkinson’s disease (PD), catalase becomes increasingly susceptible to non-enzymatic glycation, resulting in enzyme inactivation, oxidative stress, and defective mitochondrial function. This review uniquely emphasizes catalase glycation as a converging pathological mechanism that bridges metabolic and neurodegenerative disorders, underscoring its translational significance beyond prior general reviews on catalase function. In patients with metabolic diseases, glycation impairs β-cell function and insulin signaling, while in patients with neurodegeneration, it accelerates protein aggregation, mitochondrial dysfunction, and neuroinflammation. Notably, the colocalization of glycated catalase with amyloid-β and α-synuclein highlights its potential role in protein aggregation and neuronal toxicity, a mechanism not previously addressed. Therapeutically, targeting catalase glycation opens up new avenues for intervention. Natural and synthetic agents can be used to protect catalase activity by modulating glyoxalase activity, heme integrity, or carbonyl stress. Vitamins C and E, along with agents like sulforaphane and resveratrol, exert protection through complementary mechanisms, beyond ROS scavenging. Moreover, novel strategies, including Nrf2 activation and receptor for advanced glycation end products (RAGE) inhibition, are showing promise in restoring catalase activity and halting disease progression. By focusing on glycation-specific mechanisms and proposing targeted therapeutic approaches, this review positions catalase glycation as a novel and clinically relevant molecular target in patients with chronic diseases and a viable candidate for translational research aimed at improving clinical outcomes. Full article

Background/Objectives: Non-Hodgkin lymphoma (NHL) is a group of blood cancers that arise in the lymphatic nodes and other tissues after an injury to the DNA of B/T lineage and NK lymphocytes. Recently, we reported that incomptine A (IA) has in vivo antilymphoma properties. This research aimed to evaluate the effects of IA in the treatment of NHL using antilymphoma activity, Tandem Mass Tag (TMT), and bioinformatics approaches. Methods: The antilymphoma activity of IA was tested on male Balb/c mice inoculated with U-937 cells. Also, TMT, gene ontology enrichment, Reactome pathway, Kyoto Encyclopedia of Gene and Genomes pathway, molecular docking, toxicoinformatic, and pharmaceutical analyses were performed. Results: By TMT analysis of the altered levels of proteins present in the lymph nodes of Balb/c mice with NHL and treated with IA, we identified 106 significantly differentially expressed proteins (DEPs), including Il1rap, Ifi44, Timd4, Apoa4, and Fabp3 as well as Myh3, Eno 2, and H4c11. Among these, the Fhl1 result was the most important cluster altered and a potential core target of IA for the treatment of NHL. Network pharmacology studies have revealed that DEPs are associated with processes such as muscle contraction, glycolysis, hemostasis, epigenetic regulation of gene expression, transport of small molecules, neutrophil extracellular trap formation, adrenergic signaling in cardiomyocytes, systemic lupus erythematosus, alcoholism, and platelet activation, signaling, and aggregation. Computational studies revealed strong binding affinities with six proteins associated with cancer, positive pharmacokinetic properties, and no toxicity. Conclusions: Our contribution suggests that IA may be a compound with potential therapeutic effects against NHL. Full article

Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb’s impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation. Full article

Huntington’s Disease (HD) originates from the expansion of a polyglutamine (PolyQ) tract in the huntingtin protein (Htt), which can assume a coiled-coil fold (Cc). We previously found that Cc structures mediate the aggregation and toxicity of polyQ Htt. Since polyQ Htt aggregates were previously found to be internalized by cells, here we hypothesize that Cc structures might be implicated in the intercellular propagation of Htt aggregates. To test this hypothesis, we performed experiments using human cell lines expressing Htt proteins with different probabilities to acquire a Cc fold. We found that Htt with reduced Cc structures were released significantly less compared to Htt with intact Cc structures. We also found that Cc structures mediate the internalization of Htt proteins in recipient cells. Together, these results underline the importance of the Cc structure in the process of intercellular propagation of Htt polyQ aggregates and suggest that interfering with Cc formation might be a therapeutic strategy for HD. Full article

The overexpression of atypical protein kinase C-iota (PKC-ι) is a biomarker for carcinogenesis in various cell types, such as glioma, ovarian, renal, etc., manifesting as a potential drug target. In previous in vitro studies, ICA-1S and ICA-1T, experimental candidates for inhibiting PKC-ι, have demonstrated their specificity and promising efficacy against various cancers. Moreover, the in vivo studies have demonstrated low toxicity levels in acute and chronic murine models. Despite these prior developments, the binding affinities of the inhibitors were never thoroughly explored from a biophysical perspective. Here, we present the biophysical characterizations of PKC-ι in combination with ICA-1S/1T. Various methods based on molecular docking, light scattering, intrinsic fluorescence, thermal denaturation, and heat exchange were applied. The biophysical characteristics including particle sizing, thermal unfolding, aggregation profiles, enthalpy, entropy, free energy changes, and binding affinity (K_d) of the PKC-ι in the presence of ICA-1S were observed. The studies indicate the presence of domain-specific stabilities in the protein–ligand complex. Moreover, the results indicate a spontaneous reaction with an entropic gain, resulting in a possible entropy-driven hydrophobic interaction and hydrogen bonds in the binding pocket. Altogether, these biophysical studies reveal important insights into the binding interactions of PKC-ι and its inhibitors ICA-1S/1T. Full article

The cellular slime mould Dictyostelium discoideum is a soil-dwelling eukaryotic organism that undergoes distinctive morphological changes during starvation, making it a promising candidate for bioassay development. In this study, we evaluated the effects of copper (Cu) exposure on the morphological transformation of D. discoideum and performed a comparative proteomic analysis. Copper exposure on agar media delayed aggregate formation by 3.5 h compared to the controls. Approximately 280 protein spots were detected using immobilised pH gradient two-dimensional gel electrophoresis followed by silver staining. Three spots disappeared upon exposure to Cu. Based on isoelectric point and molecular weight analyses, the proteins were predicted to be formin-1, a cytoplasmic regulator of adenylyl cyclase (CRAC), and a tetratricopeptide repeat (TPR)-containing protein. Formin-1 and CRAC are involved in aggregation processes. These findings suggest that Cu disrupts aggregation-related protein expression in D. discoideum and highlight the potential of D. discoideum-based bioassays using proteomic biomarkers for environmental monitoring. Full article

Alpha-Synuclein (α-Syn) is a presynaptic neuronal protein implicated in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, primarily through its aggregation into insoluble fibrils. The extended α-Syn half-life necessitates treatment durations that are incompatible with efficient high-throughput drug screening, can risk compound stability or cause cellular toxicity. To address this, we inserted a PEST sequence, a motif known to promote rapid protein degradation, at the C-terminus of the SNCA gene using CRISPR/Cas9 to create a novel cell line with reduced α-Syn half-life. This modification accelerates α-Syn turnover, providing a robust model for studying α-Syn dynamics and offering a platform that is applicable to other long-lived proteins. Our results demonstrate a six-fold reduction in α-Syn half-life, enabling the rapid detection of changes in protein levels and facilitating the identification of molecules that modulate α-Syn production and degradation pathways. Using inhibitors of the proteasome, transcription, and translation further validated the model’s utility in examining various mechanisms that impact protein levels. This novel cell line represents a significant advancement for studying α-Syn dynamics and offers promising avenues to develop therapeutics for α-synucleinopathies. Future research should focus on validating this model in diverse experimental settings and exploring its potential in high-throughput screening applications. Full article

The misfolding and aggregation of proteins into amyloidogenic assemblies are key features of several metabolic and neurodegenerative diseases. Human insulin has long been known to form amyloid fibrils under various conditions, which affects its bioavailability and function. Clinically, insulin aggregation at recurrent injection sites poses a challenge for diabetic patients who rely on insulin therapy. Furthermore, decreased responsiveness to insulin in type 2 diabetic (T2D) patients may lead to its overproduction and accumulation as aggregates. Earlier reports have reported that various factors such as pH, temperature, agitation, and the presence of lipids or other proteins influence insulin aggregation. Our present study aims to elucidate the effects of non–micellar anionic DMPG (1,2–dimyristoyl–sn–glycero–3–phosphoglycerol) lipids on insulin aggregation. Distinct pathways of insulin aggregation and intermediate formation were observed in the presence of DMPG using a ThT fluorescence assay. The formation of soluble intermediates alongside large insulin fibrils was observed in insulin incubated with DMPG via TEM, DLS, and NMR as opposed to insulin aggregates generated without lipids. ¹³C magic angle spinning solid–state NMR and FTIR experiments indicated that lipids do not alter the conformation of insulin fibrils but do alter the time scale of motion of aromatic and aliphatic side chains. Furthermore, the soluble intermediates were found to be more cytotoxic than fibrils generated with or without lipids. Overall, our study elucidates the importance of anionic lipids in dictating the pathways and intermediates associated with insulin aggregation. These findings could be useful in determining various approaches to avoid toxicity and enhance the effectiveness of insulin in therapeutic applications. Full article

The amyloidogenic processing of amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD), primarily through the generation of amyloid-beta (Aβ) peptides, which aggregate to form toxic plaques in the brain. The regulation of amyloidogenic APP processing is a complex interplay of enzymes, proteins, and signaling pathways, all of which contribute to the development and progression of Alzheimer’s disease. Understanding the intricate mechanisms and molecular players involved in APP processing substantially enhances our knowledge of Alzheimer’s disease pathology and holds promise for the development of biomarkers of ongoing pathology at the earliest stages of Alzheimer’s disease. In this review, we aimed to investigate selected factors that regulate the amyloidogenic pathway of APP processing. Full article

Tau pathology is one of the main pathological features of Alzheimer’s disease (AD). Intracellular Tau may be released to the extracellular space upon neuron degeneration, where it has the potential to be toxic to other neurons. The propagation of Tau pathology, mediated by extracellular Tau aggregates, may underlie the pathogenesis of AD. Antibody therapies targeting Tau proteins are, therefore, considered highly promising. In this study, the cytotoxicity of extracellular Tau aggregates on SH-SY5Y cells was examined. The effect of extracellular Tau aggregates on intracellular Tau aggregation was also studied using a FRET-based assay. The extracellular Tau aggregates were found to cause intracellular Tau aggregation after entering the cells; meanwhile, ROS (reactive oxygen species) induced by Tau aggregates facilitated this process. A single-chain variable fragment antibody (scFv T1) inhibits Tau aggregation both extracellularly and intracellularly. ScFv T1 also inhibited the accumulation of ROS and alleviated the inflammation and apoptosis induced by Tau aggregates. These findings could provide experimental support for the study of neurotoxicity and related mechanisms of extracellular Tau aggregates, in addition to providing insights into the development of novel therapeutic agents to treat AD. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and limited therapeutic options. Metal-based drugs have emerged as promising alternatives in the search for effective treatments, and vanadium coordination complexes have shown significant potential due to their neuroprotective and anti-aggregant properties. This review explores the advances in the development of vanadium-based metallodrugs for AD, focusing on their ability to modulate amyloid-beta (Aβ) aggregation, oxidative stress, and neuroinflammation. Recent in vitro and in vivo studies highlight the efficacy of oxovanadium (IV) and peroxovanadium (V) complexes in inhibiting Aβ fibril formation and reducing neuronal toxicity. Additionally, the interaction of vanadium complexes with key biological targets, such as peroxisome proliferator-activated receptor gamma (PPARγ) and protein-tyrosine phosphatase 1B (PTP1B), suggests a multifaceted therapeutic approach. While these findings underscore the potential of vanadium compounds as innovative treatments for AD, further research is needed to optimize their bioavailability, selectivity, and safety for clinical applications. Full article