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Results for “Protein aggregation diseases”

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At least 19 recordsLinked to original sources
PubMed2026

Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.

Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.

Humans↗
PubMed2025

Prediction and Evaluation of Protein Aggregation with Computational Methods.

Protein and peptide aggregation has recently become one of the most studied biomedical problems due to its central role in several neurodegenerative disorders and of biotechnological importance. Multiple in silico methods, databases, tools, and algorithms have been developed to predict aggregation of proteins and peptides to better understand fundamental mechanisms of various aggregation diseases. Here, we attempt to provide a brief overview of bioinformatic methods and tools to better understand molecular mechanisms of aggregation disorders. Furthermore, through a better understanding of protein aggregation mechanisms, it might be possible to design novel therapeutic agents to treat and hopefully prevent protein aggregation diseases.

Computational Biology↗
PubMed2026

Colorimetric gold nanosensors for monitoring protein aggregation: implications for Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. It remains a major public health challenge due to the lack of early diagnostic tools and effective disease-modifying therapies. Molecularly, AD is characterized by extracellular amyloid-β (Aβ) plaques and intracellular Tau tangles, as well as soluble oligomers that are likely the neurotoxic species. However, the transient and heterogeneous nature of these oligomers makes them difficult to detect using conventional biosensing approaches. Nanomaterial-based colorimetric biosensors have emerged as promising platforms for detecting protein aggregates and discovering aggregation inhibitors. Specifically, the localized surface plasmon resonance properties of metallic nanomaterials can enable rapid, label-free, and visually detectable colorimetric sensing of molecular interactions. These features can be leveraged to monitor protein aggregation processes in real time and achieve high-throughput screening of aggregation inhibitors, which may collectively enable early detection and timely intervention of AD progression. This Review Article presents the design and engineering of gold-nanomaterial-based colorimetric biosensors for monitoring protein aggregation and highlights the current challenges and emerging opportunities for applying these nanosensors to combat AD.

Journal Article↗
PubMed1976

Inhibition of platelet aggregation by alpha1-acid glycoprotein.

In view of known abnormalities of plasma proteins in diseases showing changes in platelet aggregation, the effect of one of the major serum proteins, alpha1-acid glycoprotein, on platelet aggregation was evaluated. This protein, when added to platelet-rich plasma, markedly inhibited platelet aggregation induced by both adenosine diphosphate (ADP) and epinephrine. Transferrin, similarly studied, had no effect. These results are consistent with the hypothesis that the relative concentration of alpha1-acid glycoprotein may influence platelet aggregation in diseases associated with abnormal concentrations of this protein.

Adenosine Diphosphate↗
PubMed2026

A third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.

BACKGROUND: Tau immunotherapy has recently shown clinical promise but required high dosing. We developed NIDB-3101, a novel third-generation, high-affinity anti-tau biparatopic antibody designed for superior tau binding, aggregation inhibition, and extended half-life. METHODS: NIDB-3101 binds tau's microtubule-binding region and C-terminal domains. Various binding and cellular functional assays using recombinants, but more importantly human AD extracts were used to assess NIDB-3101 benefits. Half-life mutations impact was assessed via FcRn binding and cellular assays recycling. RESULTS: NIDB-3101 exhibited sub-nanomolar affinity, binding a broad spectrum of pathological tau species in AD homogenates, inhibited AD extracts-induced cellular effect compared to benchmark antibodies. Mutations enhanced hFcRn-mediated cellular recycling. CONCLUSIONS: NIDB-3101 captures a broad spectrum of pathological tau species leading to strong cellular efficacy using human AD extracts, supporting further clinical development as a potential disease-modifying therapy for AD and related tauopathies.

tau Proteins↗
PubMed2026

The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease.

The mutation that causes Huntington's disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyadenylation (polyA) sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington's disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time-resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers neurofilament light polypeptide (NEFL) and breast regression protein 39 (BRP39) (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies.

Animals↗
PubMed1976

Platelet membrane glycoproteins implicated in ristocetin-induced aggregation. Studies of the proteins on platelets from patients with Bernard-Soulier syndrome and von Willebrand's disease.

The antibiotic ristocetin only aggregates platelets in the presence of plasma von Willebrand factor. Platelets from patients with Bernard-Soulier syndrome do not aggregate upon addition of ristocetin although, in contrast to von Willebrand's disease, plasma levels of factor VIII complex (factor VIII clotting activity, von Willebrand factor activity, and von Willebrand antigen) are normal. The membrane surface of normal platelets was modified and compared to the surface of platelets from a patient with Bernard-Soulier syndrome in an attempt to identify the receptor involved in von Willebrand factor-ristocetin-induced aggregation. After the incubation of washed normal platelets with a preparation of ristocetin previously shown to contain a proteolytic contaminant, the aggregation response is significantly decreased on addition or normal plasma. Analaysis by gel electrophoresis of such platelets when stained for carbohydrate revealed a decrease in the relative amounts of membrane glycopro-eins. Chymotrypsin-treated normal platelets had less membrane glycoproteins in addition to giving a reduced aggregation response in ristocetin-induced aggregation. Staining of gels for protein and carbohydrate indicated that there was an extensive change in the surface of Bernard-Soulier platelets, whereas those from patients with von Willebrand's disease appeared the same as normal. Platelets from patients were labeled by the lactoperoxidase iodination technique. Not only was the relative intensity of staining of platelet-specific proteins and glycoproteins changed in Bernard-Soulier platelets, but the iodination of the glycoproteins on the membrane surface relative to other membrane constituents was lower. In contrast, platelets from patients with von Willebrand's disease showed a normal exposure of membrane components. These data suggest therefore that membrane glycoproteins may play a functional role in ristocetin-induced aggregation.

Binding Sites↗
PubMed1975

The von Willebrand syndrome.

Five patients with an original diagnosis of von Willebrand's disease are described because of their levels of factor VIII related protein, Ristocetin-induced platelet aggregation and/or family studies differed from the main group of patients with classical von Willebrand's disease. Two had normal levels of factor VIII related protein with reduced Ristocetin aggregation when this was tested in platelet rich plasma. In one, however, this was due to a plasma defect and in the other to a platelet abnormality. After cryoprecipitate infusion all abnormal tests were corrected in both these patients. The first patient, however, failed to show a secondary rise of factor VIII whereas the second showed a secondary rise of both factor VIII and of factor VIII related protein. The other three cases, who were all very severely affected, have been separated from the main group as none of their families was segregating for classical von Willebrand's disease. It is suggested that the term von Willebrand's disease should be confined to those patients who have reduced factor VIII related protein and Ristocetin aggregation, and that von Willebrand's syndrome should be used for the various sub-groups that are emerging.

Adult↗
PubMed2026

Riboregulation: a non-canonical tau function.

Almost since its discovery, tau protein has perplexed scientists and clinicians with its varied roles in physiology as well as its appearance as phosphorylated protein aggregates of various structures in many neurodegenerative diseases. Tau plays a role in microtubule stabilization, but from the earliest of studies, tau has also been observed to bind to RNA, with recent research suggesting tau has a higher affinity for some RNA species compared to microtubules. In the context of disease, tau dysfunction potentiates disruptions to RNA metabolism, including the perturbation of mRNA splicing, impairment of translation, de-repression of transposable elements, and alteration of RNA export and degradation. Tau aggregates directly sequester diverse RNA species and RNA binding proteins. Emerging evidence reinforces the characterization of tau as an RNA binding protein, highlighting questions about both the physiological and disease-related functions of this direct RNA binding. The disparate structure of tau in normal and various disease states makes teasing apart the various impacts on RNA and regulation a more difficult puzzle requiring future study. In this review, we summarize the evidence for tau's role in RNA biology, including as an RNA binding protein.

tau Proteins↗
PubMedDate not supplied

Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants.

Indomethacin failed to produce permanent ductal closure in any of four premature infants with patent ductus arteriosus to whom the drug was given. Indomethacin half-lives measured in two premature infants were 21 and 24 hours, respectively, much longer than in full-term newborns or adults. Platelet function, as measured by platelet aggregation, was grossly abnormal for two to four days after indomethacin administration, normal values returning only by the ninth and tenth days. Gastrointestinal bleeding and transient renal dysfunction occurred in one infant. Measurement of plasma indomethacin concentrations in sick, low-birthweight infants could help guide indomethacin dose and dosage interval, prevent drug accumulation, and reduce toxicity. Further studies of potential toxicity seem to be indicated before instituting widespread indomethacin administration for ductal closure in premature infants.

Blood Platelet Disorders↗
PubMed2024

Molecular Signatures of Neurodegenerative Diseases Identified by Proteomic and Phosphoproteomic Analyses in Aging Mouse Brain.

A central hallmark of neurodegenerative diseases is the irreversible accumulation of misfolded proteins in the brain by aberrant phosphorylation. Understanding the mechanisms underlying protein phosphorylation and its role in pathological protein aggregation within the context of aging is crucial for developing therapeutic strategies aimed at preventing or reversing such diseases. Here, we applied multi-protease digestion and quantitative mass spectrometry to compare and characterize dysregulated proteins and phosphosites in the mouse brain proteome using three different age groups: young-adult (3-4 months), middle-age (10 months), and old mice (19-21 months). Proteins associated with senescence, neurodegeneration, inflammation, cell cycle regulation, the p53 hallmark pathway, and cytokine signaling showed significant age-dependent changes in abundances and level of phosphorylation. Several proteins implicated in Alzheimer's disease (AD) and Parkinson's disease (PD) including tau (Mapt), Nefh, and Dpysl2 (also known as Crmp2) were hyperphosphorylated in old mice brain suggesting their susceptibility to the diseases. Cdk5 and Gsk3b, which are known to phosphorylate Dpysl2 at multiple specific sites, had also increased phosphorylation levels in old mice suggesting a potential crosstalk between them to contribute to AD. Hapln2, which promotes α-synuclein aggregation in patients with PD, was one of the proteins with highest abundance in old mice. CD9, which regulates senescence through the PI3K-AKT-mTOR-p53 signaling was upregulated in old mice and its regulation was correlated with the activation of phosphorylated AKT1. Overall, the findings identify a significant association between aging and the dysregulation of proteins involved in various pathways linked to neurodegenerative diseases with potential therapeutic implications.

Animals↗
PubMed2025

Benchmark for Quantitative Global and Redox Proteomics Analysis by Combining Protein-Aggregation Capture and Data Independent Acquisition.

Oxidative damage plays a critical role in various diseases including cardiovascular and neurological disorders. Thiol redox reactions, acting as oxidative stress sensors, influence protein structure and function. Redox proteomics, based on the differential alkylation of cysteine sites followed by mass spectrometry, enables the comprehensive analysis of thiol redox status in cells and tissues. However, these approaches require extensive sample manipulation and are not compatible with data-independent acquisition techniques. Here, we introduce PACREDOX, an innovative strategy based on protein aggregation capture (PAC), and demonstrate its compatibility with library-free DIA. Compared with traditional methods such as FASILOX, PACREDOX reduces preparation time and costs while maintaining thiol and proteome coverage. To enable library-free DIA, we corrected in silico spectral libraries in DIA-NN using experimental retention time data from methylthiolated-Cys peptides. PACREDOX with DIA was benchmarked against FASILOX in a myocardial infarction model, yielding the same biological insights, while enhancing peptide and protein coverage. Our results underscore the potential and efficiency of this methodology for studying oxidative damage. Overall, PACREDOX offers an automatable, high-throughput, and cost-effective strategy for redox proteomics.

Proteomics↗
PubMed2026

Cryo-EM structure of TGFBIp fibrils driven by a corneal dystrophy-linked mutation enables design of peptide inhibitors of aggregation.

Corneal dystrophy is a heterogeneous group of diseases which manifests clinically by progressive corneal opacity and diminishing visual acuity. A group of corneal dystrophies are linked to autosomal dominant mutations in transforming growth factor β-induced protein (TGFBIp) and characterized by extracellular amyloid-positive deposits of unknown molecular structure. Here, we determined the cryogenic-electron microscopy (cryo-EM) structure of amyloid fibrils formed by the TGFBIp FAS1-4 domain with corneal dystrophy-linked mutation V624M. The L569 to N609 fibril core, which includes the Y571-R588 segment enriched in patient corneal deposits, forms symmetrical protofilaments with internal solvent channels. Leveraging this structure, we designed peptide inhibitors intended to bind onto fibril ends to block elongation, targeting the unequal growth of symmetrical protofilaments. Our G1 and H4 inhibitors exhibit concentration-dependent reduction of TGFBIp FAS1-4 aggregation as assessed by Thioflavin T, solubility fractionation, and electron microscopy. Our work illustrates how fibril structures can guide rational inhibitor design and suggests the targeting of protein aggregates as a therapeutic approach for corneal and ocular diseases.

betaIG-H3 Protein↗
PubMed1978

Serum genetic markers in a Newfoundland isolate with a familial aggregate of Hodgkin's disease.

Inherited genetic markers on the immunoglobulins and three other serum proteins were investigated in members of an isolated Newfoundland community. The frequencies found were compared with those from Europe. Whilst the incidence of the commonest variant forms were typically 'European', the occurrence of rare phenotypes pointed towards specific admixture from American Indians and Scandinavia. A possible contribution of these rare alleles, and of others, to pathogenesis in a familial aggregate of Hodgkin's disease within this community is discussed.

Gene Frequency↗
PubMed2012

Role of genes linked to sporadic Alzheimer's disease risk in the production of β-amyloid peptides.

Alzheimer's disease (AD) is characterized by the presence of toxic protein aggregates or plaques composed of the amyloid β (Aβ) peptide. Various lengths of Aβ peptide are generated by proteolytic cleavages of the amyloid precursor protein (APP). Mutations in many familial AD-associated genes affect the production of the longer Aβ42 variant that preferentially accumulates in plaques. In the case of sporadic or late-onset AD, which accounts for greater than 95% of cases, several genes are implicated in increasing the risk, but whether they also cause the disease by altering amyloid levels is currently unknown. Through loss of function studies in a model cell line, here RNAi-mediated silencing of several late onset AD genes affected Aβ levels is shown. However, unlike the genes underlying familial AD, late onset AD-susceptibility genes do not specifically alter the Aβ42/40 ratios and suggest that these genes probably contribute to AD through distinct mechanisms.

Age of Onset↗
PubMed2026

Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.

Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.

Journal Article↗
PubMed1979

Platelet receptors for human Factor VIII/von Willebrand protein: functional correlation of receptor occupancy and ristocetin-induced platelet aggregation.

Previous studies of von Willebrand disease indicate that a deficiency of blood clotting Factor VIII/von Willebrand factor (FVIII/vWF) activity is responsible for the failure of platelets to participate fully in the initial stages of hemostasis. We have recently identified specific FVIII/vWF binding sites on platelets, suggesting that the interaction of these sites with FVIII/vWF may be functionally important in the development of platelet clumps. We have now studied how different ristocetin concentrations, various known platelet aggregation inhibitors, and the exposure of platelets to proteases affect the ability of platelets to bind FVIII/vWF and to form aggregates. Our results demonstrate a highly significant linear correlation between the degree of FVIII/vWF receptor binding and the extent of ristocetin-induced platelet aggregation. Because neither FVIII/vWF binding nor platelet aggregation occurs after platelets are exposed to low concentrations of proteases, the FVIII/vWF receptors must be in the platelet membrane. We conclude that the interaction between FVIII/vWF protein and its receptors on the platelet membrane is an important mechanism by which platelet aggregation occurs during primary phase hemostasis.

Binding, Competitive↗