Search Results (1,302)

Transthyretin amyloidosis (ATTR) is a multisystemic disorder associated with extracellular accumulation of misfolded transthyretin (TTR) protein forming insoluble amyloid deposits. Depending on the TTR genotype, ATTR is classified as hereditary ATTR (ATTRv) with pathogenic gene variants and wild-type ATTR (ATTRwt) with a normal TTR genotype. Two cardinal clinical manifestations of ATTR are amyloid cardiomyopathy and peripheral neuropathy, but multisystemic deposition of amyloid may also manifest with ocular and leptomeningeal amyloidosis, various orthopedic complications (carpal tunnel syndrome, spinal stenosis), nephropathy, and gastrointestinal and pulmonary amyloidosis. The natural history of untreated ATTR is characterized by progressive worsening and 25% of patients may die within 24 months from the onset. The first treatment for ATTR was liver transplantation which slows the disease progression, but its use was limited by the scarcity of available liver allografts and complex post-transplant morbidities associated with immunosuppression and various metabolic disturbances. Recent introduction of TTR stabilizers and gene silencing has significantly changed the outcomes and reduced ATTR-related morbidities and mortality, and early diagnosis remains important for improved outcomes. In our narrative expert review, we are discussing epidemiological and clinical features of ATTR, its pathophysiology and available treatments as rapidly progressive fatal disease is being transformed into a treatable chronic disease. Full article

Background: Type 2 diabetes is projected to affect millions of people annually as the number of cases rises year on year. This includes children. Treating diabetes and its related comorbidities has a huge economic impact and puts pressure on healthcare providers. Understanding the disease at a molecular level is key for developing better therapeutics. The protein Islet Amyloid Polypeptide (IAPP) or amylin is important for glucose regulation; however, it is also instrumental in type 2 diabetes pathology. Human IAPP can misfold into oligomers and amyloid fibrillar aggregates within pancreatic islets, promoting β-cell dysfunction and death, contributing to progressive insulin deficiency and worsening hyperglycaemia. Methods: Based on previous studies on mutations at residues 18, 28 and 31,we have designed three novel IAPP analogues (two double and one triple mutant) to assess whether the combined amino acid substitutions impact fibril formation, solubility and toxicity. Results: All three of our analogues show a reduced propensity to aggregate and are more soluble than wild type IAPP. Compared with pramlintide, a clinically prescribed synthetic analogue of human amylin, all of our analogues appeared to have similarly reduced toxicity and improved solubility relative to human IAPP. Additionally, two of our analogues exhibited a markedly slower rate of fibril formation. Conclusions: Our results highlight the importance of targeting multiple residues as a promising strategy for developing improved diabetes therapeutics in the future. Full article

Background/Objectives: Protein misfolding and amyloid fibril formation underlie several degenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Alpha-1 antitrypsin (A1AT), a serpin protein, is particularly prone to misfolding, with polymerization and aggregation implicated in alpha-1 antitrypsin deficiency and associated hepatic and pulmonary disorders. In this study, we examined the structural changes in A1AT induced by the fluorinated alcohol, trifluoroethanol (TFE), and assessed the inhibitory effects of two natural polyphenols, amentoflavone (AMF) and theaflavin (TF), on aggregation and fibril formation. Methods: A library of selected phytocompounds was virtually screened against the crystal structure of A1AT (PDB 3NE4) using AutoDock Vina to elucidate their binding affinity towards it. Based on binding affinities, two compounds, AMF and TF, were selected for further studies. Protein aggregation was induced with TFE, and the protective effects of AMF and TF were evaluated using protease inhibitory activity, intrinsic fluorescence, turbidity, Rayleigh scattering, ANS fluorescence, and ThT fluorescence assays. Furthermore, 100 ns molecular dynamics simulation and MM-PBSA calculations were performed to assess the stability and binding interactions of the A1AT–ligand complexes. Results: Pre-treatment of A1AT with AMF or TF significantly inhibited TFE-induced aggregation in a dose-dependent manner, with AMF being consistently more effective. ThT fluorescence analysis revealed a ~60–65% decrease in aggregate formation upon treatment with polyphenols, with IC₅₀ values estimated at ~40 µM for AMF and ~50 µM for TF, both of which are statistically significant. Molecular docking and 100 ns molecular dynamics simulation also revealed stable A1AT–polyphenol interactions, with AMF exhibiting greater binding affinity and greater attenuation of solvent-induced conformational perturbation. Conclusions: Collectively, our findings show that TFE causes A1AT misfolding via a molten globule-like intermediate, resulting in fibril formation at 30–40% TFE, and natural polyphenols AMF and TF inhibited aggregation in a concentration-dependent manner. These observations suggest the potential of AMF and TF as lead scaffolds for anti-aggregation strategies, as modulators of amyloidogenic processes. Full article

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis and cellular survival under stress conditions. Clinically relevant human pathogenic fungi include opportunistic fungi, dimorphic fungi, dermatophytes, Mucorales, and other pathogenic groups. HSPs, including Hsp90, Hsp70, Hsp60, Hsp40, and Hsp110, are essential for the correct nascent protein folding, aggregation prevention, and degradation of misfolded polypeptides. Fungal pathogens frequently encounter environmental and host-imposed stresses, including oxidative stress, temperature fluctuations, and antifungal treatments. This review synthesizes and critically analyzes current evidence on the role of HSP families in essential processes linked to fungal virulence, including morphogenetic transitions, biofilm formation, maintenance of cell wall integrity, and interactions with host immune cells. Beyond their canonical chaperone functions, HSPs act as central mediators in pathogenic processes, such as morphogenesis transitions, biofilm formation, cell wall integrity, and interactions with host immune cells. Hsp90 stabilizes key signaling proteins involved in stress responses, morphogenesis, and antifungal resistance, while Hsp60 and Hsp70 contribute to mitochondrial function, cell wall integrity, and immune modulation. Disruption of these chaperones impairs growth, reduces virulence, and increases susceptibility to antifungal agents. The rise of antifungal resistance underscores the urgent need for new therapeutic strategies. Targeting fungal HSPs has emerged as a promising approach due to their essential roles in stress tolerance and pathogenesis. Hsp90 inhibitors, including geldanamycin derivatives and other small molecules, have demonstrated the ability to impair fungal growth, reduce virulence traits, and sensitize resistant strains to conventional antifungal drugs. Combining HSP inhibitors with existing antifungal drugs represents a potential strategy to overcome resistance and improve treatment outcomes. This review summarizes the current knowledge on HSPs in pathogenic fungi, focusing on their roles in stress adaptation, virulence, host-pathogen interaction, antifungal resistance, and their potential as targets for novel antifungal therapies. Full article

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG trinucleotide in the exon 1 of the huntingtin gmodellerene. This abnormal expansion produces a mutant huntingtin (mHTT) protein with extended polyglutamine (polyQ) tracts. Although the molecular mechanisms underlying HD onset and progression remain poorly understood, aberrant folding, aggregation, and membrane interactions of mHTT are considered central to disease pathogenesis. In this study, we used molecular dynamics (MD) simulations to investigate the structural properties, dimerization propensity, and membrane lipid interaction of mHTT carrying 70 polyQ repeats (mHTT-Q70). Our analyses revealed that mHTT-Q70 retains partially structured α-helical conformations with increased flexibility within the polyQ domain, thus being predisposed to misfolding. Coarse-grained MD simulations further revealed a strong tendency of mHTT-Q70 to dimerize, indicating that early oligomerization may represent a critical step in protein aggregation. Interestingly, we show that membrane cholesterol content dose-dependently promotes dimeric mHTT-Q70—but not monomeric mHTT-Q70—association with neuronal membrane models, which was observed for 70% of simulation time at 40% cholesterol content. Such a cholesterol-dependent membrane binding of dimeric mHTT-Q70 suggests that membrane lipid composition may represent a critical checkpoint in the early stages of mHTT-Q70 aggregation, and of cytotoxicity thereof. Moreover, distinct neuronal membrane lipids like phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine differently contributed to mHTT-Q70 binding, highlighting the complexity of such a lipid-dependent modulation. Taken together, these findings underscore the dynamic interplay between polyQ-driven misfolding, dimerization, and membrane lipids in HD pathogenesis, suggesting that modulation of membrane composition, and in particular of cholesterol levels, may be a novel action point to design therapeutic drugs for HD. Full article

Neurodegenerative disorders, including Parkinson’s, Alzheimer’s, and multiple sclerosis, are significant global health issues characterized by escalating neuronal dysfunction and cognitive decline. Studies suggest that microbial toxins originating from fungi and bacteria may contribute to neurodegenerative processes by altering neuronal homeostasis in several ways. Toxins formerly associated with infectious diseases have now been associated with neuroinflammation, oxidative stress, and protein misfolding, all of which are common in neurodegenerative diseases. According to recent studies, microbial toxins generated by the gut microbiota may cross the blood–brain barrier and possibly contribute to neuroinflammatory cascades linked to the development of neurodegenerative diseases. The complex interplay of microbial metabolites, microbial responses, and mitochondrial dysfunction demonstrates the diverse character of neurodegenerative processes. This review delves into the current understanding of microbial toxins, which are produced by diverse bacteria and can have a direct or indirect impact on neuronal health via multiple signaling pathways. Understanding the signaling mechanisms of microbial and toxin-mediated neurodegenerative diseases could result in the development of effective alternative therapeutics for neurological disorders. Full article

Oxidative stress causes brain damage contributing to neurodegenerative and vascular diseases. In Alzheimer’s disease (AD), elevated oxidative stress and mitochondrial damage are closely linked to misfolded protein accumulation. ROS also plays a major role in ischemic brain injury, particularly during reperfusion, impairing the blood–brain barrier and highlighting the association between vascular pathology and AD. To investigate perturbations in brain cells occurring in mixed dementia (AD combined with vascular dementia components), we used a triple culture system comprising neurons, astrocytes, and microglia and induced neuronal injury by combining LPS and H₂O₂ exposures. Cell viability assays revealed that neuronal death occurred mainly through apoptosis and DNA damage. In neurons and astrocytes exposed to LPS+H₂O₂, the expression of NADPH oxidase isoform 2, a major source of ROS, increased, along with FOXO3 and SOD2, a key mitochondrial ROS scavenger. Indeed, these changes were accompanied by altered mitochondrial morphology and integrity, as well as reduced neurite extension and thickness. The treatment with extracellular vesicles (EVs) derived from amniotic fluid stem cells was tested due to their rich content of antioxidant molecules. Interestingly, EVs reversed the negative effects of LPS+H₂O₂, suggesting the protective role against neuronal injury in vitro may be mediated by the EV-cargo. Full article

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies. Full article

Suicide is a major public health concern and cause of death worldwide. While progress has been made in understanding molecular pathways involved in suicide, much more work is needed to identify clinically useful biomarkers of suicidality. Disturbed cellular proteostasis and aggregation of specific misfolded proteins are established pathological factors of neurodegenerative diseases. Increasing evidence also suggests that such aggregates often occur in patients with chronic mental illnesses. Recently, genes related to disturbed proteostasis showed differential methylation in individuals who died by suicide compared to controls. These include five genes encoding proteins that aggregate in neurodegenerative and/or mental illness: CRMP1 (also called DPYSL1), DISC1, MAPT (encoding the Tau protein), PRKN (also called PARK2, encoding Parkin), and SOD1. Given the possibility that altered methylation in these genes could affect expression of the proteins they encode, we aimed to review evidence for whether disturbed proteostasis may be a point of overlap between suicidality, neurodegenerative disease, and/or mental illnesses. Epigenetic changes in most of these genes also occur in other neurological disorders. Autophagy, and, to a lesser extent, the ubiquitin–proteasome system, are emerging as potentially impaired in individuals with suicidal tendencies and individuals who died by suicide. Based on this accumulated data, we hypothesise that disturbed proteostasis is likely to be a pathological component of suicidality. It is also plausible that this may lead to the accumulation of aggregated proteins in a similar manner to, and potentially overlapping with, those seen in major mental illnesses. If true, this would have consequences for potential identification of biomarkers for suicidality and should be a priority for future research in the field. Full article

Due to the substantial secretory burden, bovine mammary epithelial cells (BMECs) are highly susceptible to endoplasmic reticulum (ER) stress caused by the accumulation of misfolded proteins when protein-folding capacity is overwhelmed. However, how ATF3 regulates ER stress-induced impairment of milk synthesis and apoptosis in BMECs, particularly through its direct transcriptional targets, remains poorly understood. In this study, we investigated the protective role of activating transcription factor 3 (ATF3) against ER stress-induced impairment of milk synthesis in BMECs. Using a tunicamycin-induced ER stress model, we overexpressed ATF3 in BMECs and performed integrated RNA-seq and ChIP-seq analyses to elucidate the underlying molecular mechanisms. Our results indicated that ER stress disrupted milk protein and fat synthesis in BMECs by suppressing the expression of CSN2, FASN, FABP3 and promoting apoptosis via upregulation of BAX and CASP3. ATF3 overexpression effectively attenuated these effects, reducing apoptosis and restoring the expression of milk fat-related genes. Transcriptomics demonstrated that ATF3 activated MAPK and PI3K-Akt signaling and lipid metabolism pathways, significantly upregulating key genes involved in fatty acid uptake, transport, and metabolism (CD36, SLC27A1, ACSL1, PLIN1). Integrated RNA-seq and ChIP-seq analyses identified 81 overlapping genes, with RASGRP2, PRKACB, MAP3K5, and DUSP10 confirmed as direct transcriptional targets of ATF3, mediating its regulation of the MAPK pathway. Collectively, these findings elucidate the protective role of ATF3 against ER stress-induced lactation disruption and offer potential molecular targets for enhancing lactation resilience in dairy cattle under stress. Full article

The causative event in transmissible spongiform encephalopathies is the misfolding of the prion protein (PrP), a process influenced, in a way that is not yet fully understood, by transition metal ions, particularly copper, which modulate folding, aggregation, and redox activity. In this study, we investigated the interaction of copper(II) ions with the prion fragment PrP(95–126), which includes the non-octarepeat high-affinity sites His96 and His111, as well as an amyloidogenic tail involved in PrP misfolding and membrane interaction. UV–vis and circular dichroism analyses revealed the predominant formation of a 1:1 Cu/PrP(95–126) complex, accompanied by modest restructuring, consistent with an increased aggregation propensity upon copper binding. The Cu/PrP(95–126) complexes exhibited limited redox activity toward catechol substrates, which was further reduced in membrane-mimetic systems such as SDS micelles and large unilamellar vesicles (LUVs). His96 appears not to play a critical role in copper coordination or redox activation. This study explores the coordination modes and reactivity of copper(II) with PrP, as well as employing a membrane mimic, aspects that are still highly controversial in the literature, providing insights for further in vitro studies. Full article

Chronic kidney disease (CKD) is an established risk factor for Parkinson’s disease (PD), but the molecular mechanisms linking these two conditions remain elusive. We performed a systems biology analysis by retrieving high-confidence gene–disease associations from DisGeNET v7.0 (PD: score ≥ 0.8, EI ≥ 0.4; CKD: score ≥ 0.6, EI ≥ 0.4) and constructing a protein–protein interaction (PPI) network via STRING v11.5 (confidence ≥ 0.700). Direct “molecular bridges” between CKD and PD proteins were identified and validated using independent databases. To corroborate biological feasibility, candidate proteins were cross-referenced with ExoCarta and Vesiclepedia databases for exosomal localization. Functional enrichment, tissue expression, and pathway analyses were conducted. Despite zero gene overlap (64 PD genes, 17 CKD genes), the PPI network showed significant convergence (81 nodes, 280 edges, PPI enrichment p < 1.0 × 10⁻¹⁶). Fifteen high-confidence molecular bridges were identified, including the Apolipoprotein A1 (APOA1)–α-synuclein (SNCA) interaction (combined score 0.883), which was independently validated by IntAct. Functional enrichment revealed specific association of APOA1–SNCA with “amyloid fiber formation” (false discovery rate (FDR) = 0.038). Both APOA1 and SNCA are annotated as exosome components (Kyoto Encyclopedia of Genes and Genomes (KEGG) ko04147) and were confirmed as consistent cargo in plasma, urine, and platelet-derived extracellular vesicles within proteomic databases (ExoCarta IDs: 335, 6622). Global pathway analysis highlighted inflammation, oxidative stress, and the advanced glycation end product (AGE)–receptor for AGE (RAGE) pathway. We propose an integrative model wherein CKD-induced dysregulation of APOA1 promotes α-synuclein misfolding and aggregation, and the co-packaging of these proteins into exosomes provides a plausible vehicle for kidney-to-brain propagation. This framework offers testable hypotheses and potential therapeutic targets for PD-CKD comorbidity. Full article

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article

Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy–neuroinflammation axis in neurodegenerative disorders. Full article

Prion diseases are fatal neurodegenerative disorders that affect humans and animals, caused by the conformational conversion of the normal cellular prion protein (PrP^C) into its misfolded, infectious isoform PrP^Sc. Recently, camel prion disease (CPrD) was identified in dromedary camels (Camelus dromedarius) in Algeria. Due to the potential implications for animal and human health, as well as the possible socio-economic impact in Mediterranean regions where camels play a pivotal role as a source of food, in-depth characterization of camel prions is important to increase our understanding of camel prion disease. We developed a neuronal cell line model for studying the molecular features of camel prion infection. We genetically edited mouse neuronal CAD5 cells to generate CAD5 PrP knockout (KO) cells. We then used lentiviral transduction to generate CAD5 cells expressing camel PrP (CAD5-camel-PrP). Following infection of these cells with a CPrD-positive camel brain homogenate, we observed PrP^Sc signals at various passages, as indicated by immunoblotting analysis. RT-QuIC (Real-Time Quaking-Induced Conversion) assays further supported these findings, demonstrating transient prion conversion activity in the CPrD-infected CAD5-camel-PrP cells. Taken together, our data describe the first neuronal cell line permissive to camel prion infection, a novel in vitro tool for mechanistic studies of camel prion disease. Full article