Misfolded Research Articles

Complement C3d enables cell-mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells

Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC-I presentation, and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell-mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.

Structural Commonalities Determined by Physicochemical Principles in the Complex Polymorphism of the Amyloid State of Proteins.

Advances in solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryoEM) have revealed the polymorphic nature of the amyloid state of proteins. Given the association of amyloid with protein misfolding disorders, it is important to understand the principles underlying this polymorphism. To address this problem, we combined computational tools to predict the specific regions of the sequence forming the β-spine of amyloid fibrils with the availability of 30, 83 and 24 amyloid structures deposited in the Protein Data Bank (PDB) and Amyloid Atlas (AA) for the amyloid β (Aβ) peptide, α-synuclein (αS), and the 4R isoforms of tau, associated with Alzheimer's disease, Parkinson's disease, and various tauopathies, respectively. This approach enabled a statistical analysis of sequences forming β-sheet regions in amyloid polymorphs. We computed for any given sequence residue n the fraction of PDB/AA structures in which that residue adopts a β-sheet conformation (Fβ(n)) to generate an experimental, structure-based profile of Fβ(n) vs n, which represents the β-conformational preference of any residue in the amyloid state. The peaks in the respective Fβ(n) profiles of the three proteins, corresponding to sequence regions adopting more frequently the β-sheet structural core in the various fibrillar structures, align very well with the peaks identified with five predictive algorithms (ZYGGREGATOR, TANGO, PASTA, AGGRESCAN, WALTZ). These results indicate that, despite amyloid polymorphism, sequence regions most often forming the structural core of amyloid have high hydrophobicity, high intrinsic β-sheet propensity and low electrostatic charge across the sequence, as rationalised and predicted by the algorithms.

Liquid–liquid phase separation in neurodegenerative diseases: An updated understanding

Liquid–liquid phase separation (LLPS), once understood merely as a physicochemical phenomenon, has emerged over the past decade as a critical player in life processes. LLPS provides a novel framework for understanding the structure, function, and spatiotemporal regulation of intracellular biomolecules. Through LLPS, biomolecules within cells can spontaneously assemble into membraneless compartments, which allow precise regulation of biochemical reactions and influence critical cellular processes such as signal transduction and gene expression. Despite its recognized significance in basic biological research, the role of LLPS in human disease is still an area worthy of continued exploration. Currently, the most studied disorders in relation to LLPS are neurodegenerative diseases and cancer. In neurodegenerative diseases, LLPS is closely linked to protein misfolding and aggregation, processes that can lead to the formation of toxic assemblies, ultimately causing neuronal damage and death. In cancer, aberrant LLPS may contribute to the dysregulation of signaling pathways, promoting uncontrolled cell proliferation and metastasis. This review highlights recent advances regarding the role of LLPS in the pathogenesis of neurodegenerative diseases, discussing its function in these pathological conditions and proposing directions for future research. As research progresses, the potential role of LLPS in other human diseases will likely be uncovered, offering new avenues for diagnosis and therapy. Therefore, further investigation into the mechanisms of LLPS and its involvement in disease pathology will be crucial for advancing our understanding of human health and disease.

Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels.

ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through which mechanisms they contribute to cancer. Here we show that all truncating mutations analyzed at endogenous levels exhibit loss-of-function, with longer variants retaining partial activity. Regarding missense mutations, we show that 27/82 ZNRF3 variants in the RING and R-Spondin domain structures, lead to (partial) loss-of-function/hyperactivation. Mechanistically, defective R-Spondin domain variants appear to undergo endoplasmic-reticulum-associated degradation due to protein misfolding, leading to reduced protein levels. They fail to reach the membrane correctly, which can be partially restored for several variants by culturing cells at 27 °C. Although RING and R-Spondin domain mutations in RNF43/ZNRF3 are often considered to possess dominant-negative oncogene-like activity in cancers, our findings challenge this notion. When representative variants are heterozygously introduced into endogenous ZNRF3, their impact on β-catenin signaling mirrors that of heterozygous knockout, suggesting that the supposed dominant-negative effect is non-existent. In other words, so-called "hyperactivating" ZNRF3/RNF43 mutations behave as classical loss-of-function mutations at endogenous levels.

Chronic gastroesophageal reflux dysregulates proteostasis in esophageal epithelial cells

Background and aimsGastroesophageal reflux disease (GERD) is a common digestive disorder that is characterized by esophageal tissue damage produced by exposure of the esophageal lining to the gastric refluxate. GERD can raise the risk of multiple serious complications including esophageal tumors. At the molecular levels, GERD-affected tissues are characterized by strong oxidative stress and the formation of reactive isolevuglandins (isoLGs). These products of lipid peroxidation rapidly interact with cellular proteins forming protein adducts. Here, we investigated the interrelationship between isoLG adduction and aggregation of cellular proteins. MethodsProtein misfolding and aggregation were analyzed using multiple protein misfolding and aggregation assays. Pathological consequences of protein adduction and aggregation were studied using human and murine esophageal tissues. Surgical model of esophageal reflux injury and L2-IL1β transgenic mice were employed to investigate the mechanisms of protein misfolding and aggregation. ResultsOur studies demonstrate that gastroesophageal reflux causes protein misfolding and aggregation that is associated with severity of GERD. Dysregulation of proteostasis induces ferroptotic cell death and is mediated by modification of cellular proteins with reactive isoLGs that can be prevented by isoLG scavengers. ConclusionsGERD causes dysregulation of cellular proteostasis, accumulation of isoLG protein adducts, misfolded and aggregated proteins that promote ferroptotic cell death. Taken together, this study suggests that GERD has similarities to other known pathological conditions that are characterized by protein misfolding and aggregation.

Protein misfolding by manganese (III) oxide nanoparticles generated by pulsed laser ablation in liquids

The high demand for metal oxide nanoparticles for applications in various fields has led to increased research and investigation. However, one tends to neglect the harmful effects of these synthesized nanoparticles on human health. Mn2O3 nanoparticles are a type of metal oxide nanoparticle that can have harmful effects if ingested or inhaled. In this study, Mn2O3 nanoparticles are synthesized using laser ablation at the manganese-water interface. The structural and optical properties of the nanoparticles are studied using HR-TEM, Micro-Raman, Ultraviolet–visible (UV–vis), and Photoluminescence spectroscopy. The cubic bixbyite α-Mn2O3 nanoparticles produced by laser ablation are used for studying their role in inhibiting or promoting protein fibrillation. Different concentrations of α-Mn2O3 nanoparticles are added to Human serum albumin (HSA) protein, where the fibrillation of the protein is investigated with the help of thioflavin T (ThT) dye using fluorescence spectroscopy. The protein misfolded on adding the nanoparticles that could be seen in the images obtained using fluorescence microscopic imaging, where the HSA forms a dense network of fibrils. In-vitro studies reveal that the increasing concentration of the nanoparticles increases the fibrillation of the HSA protein.

Characterization of intact FeoB in a lipid bilayer using styrene-maleic acid (SMA) copolymers.

The acquisition of ferrous iron (Fe2+) is crucial for the survival of many pathogenic bacteria living within acidic and/or anoxic conditions such as Vibrio cholerae, the causative agent of the disease cholera. Bacterial pathogens utilize iron as a cofactor to drive essential metabolic processes, and the primary prokaryotic Fe2+ acquisition mechanism is the ferrous iron transport (Feo) system. In V. cholerae, the Feo system comprises two cytosolic proteins (FeoA, FeoC) and a complex, polytopic transmembrane protein (FeoB) that is regulated by an N-terminal soluble domain (NFeoB) with promiscuous NTPase activity. While the soluble components of the Feo system have been frequently studied, very few reports exist on the intact membrane protein FeoB. Moreover, FeoB has been characterize almost exclusively in detergent micelles that can cause protein misfolding, disrupt protein oligomerization, and even dramatically alter protein function. As many of these characteristics of FeoB remain unclear, there is a critical need to characterize FeoB in a more native-like lipid environment. To address this unmet need, we employ styrene-maleic acid (SMA) copolymers to isolate and to characterize V. cholerae FeoB (VcFeoB) encapsulated by a styrene-maleic acid lipid particle (SMALP). In this work, we describe the development of a workflow for the expression and the purification of VcFeoB in a SMALP. Leveraging mass photometry, we explore the oligomerization of FeoB in a lipid bilayer and show that the VcFeoB-SMALP is mostly monomeric, consistent with our previous oligomerization observations in surfo. Finally, we characterize the NTPase activity of VcFeoB in the SMALP and in a detergent (DDM), revealing higher NTPase activity in the presence of the lipid bilayer. When taken together, this report represents the first characterization of any FeoB in a native-like lipid bilayer and provides a viable approach for the future structural characterization of FeoB.

Dynamic fibrillar assembly of αB-crystallin induced by perturbation of the conserved NT-IXI motif resolved by cryo-EM

αB-crystallin is an archetypical member of the small heat shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we ablate a conserved IXI-motif located within the N-terminal (NT) domain of human αB-crystallin implicated in subunit exchange dynamics and client sequestration. This results in a profound structural transformation, from highly polydispersed caged-like native assemblies into an elongated fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of this variant facilitates interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveil several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in αB-crystallin assembly, polydispersity, and chaperone activity.

Cancers adapt to their mutational load by buffering protein misfolding stress

In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.

Hepatovirus translation requires PDGFA-associated protein 1, an eIF4E-binding protein regulating endoplasmic reticulum stress responses.

The overexpression and misfolding of viral proteins in the endoplasmic reticulum (ER) may cause cellular stress, thereby inducing a cytoprotective, proteostatic host response involving phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α). Here, we show that hepatitis A virus, a positive-strand RNA virus responsible for infectious hepatitis, adopts a stress-resistant, eIF2α-independent mechanism of translation to ensure the synthesis of viral proteins within the infected liver. Cap-independent translation directed by the hepatovirus internal ribosome entry site and productive hepatovirus infection of mice both require platelet-derived growth factor subunit A (PDGFA)-associated protein 1 (PDAP1), a small phosphoprotein of unknown function with eIF4E-binding activity. PDAP1 also interacts with eIF1A and is essential for translating stress-resistant host messenger RNAs that evade the proteostatic response to ER stress and that encode proteins promoting the survival of stressed cells.

Predictive value of urine misfolded protein in preeclampsia in twin pregnancies.

To assess the utility of urinary misfolded proteins (MP) in predicting preeclampsia (PE) in high-risk twin pregnancies. A prospective study was conducted on 600 high-risk twin pregnancies at Shanghai First Maternity and Infant Hospital from March to August 2021. Clinical data were collected, and urinary MP levels were measured. Subsequently, fetal outcomes were monitored. The patients were categorized into three groups based on the presence of PE: unaffected PE group, early-onset PE (ePE) group (gestational age < 34weeks), and late-onset PE (lPE) group (gestational age ≥ 34weeks). The predictive value of MP in PE was evaluated using analysis of variance, Chi-square test, and ROC curve analysis. A total of 464 twin pregnancies were included in the study, among which 66 cases (14.2%) developed PE, including 19 cases of ePE (4.1%) and 47 cases (10.1%) of lPE. Significant differences were found in maternal age, pre-pregnancy body mass index (BMI), BMI ≥ 28km/m2, mean systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP), MAP ≥ 85mmHg, history of PE, history of chronic hypertension, and positive urine protein. The maternal and fetal complications of twin pregnancies with PE were higher than those without PE (P < 0.05). When maternal factors (MF), MAP, and MP were used to predict ePE and lPE alone, the area under the ROC curve of MF was the largest, at 0.739 (95% CI 0.619-0.860) and 0.692 (95% CI 0.603-0.782), respectively. The area under the ROC curve of the combination of the three factors was 0.770 (95% CI 0.703-0.837), higher than that of a single index. In addition, MP predicted the positive predictive value (PPV) and negative predictive value (NPV) of PE from 12 to 15+6 gestational weeks as 57.9% and 89.2%, respectively; from 16 to 27+6 gestational weeks as 36.2% and 89.9%, respectively; and during the 12-27+6 gestational weeks as 42.4% and 92.2%, respectively. The detection of MP in the urine of women with twin pregnancies is a non-invasive and convenient method for predicting PE. If the test result is positive, enhanced monitoring and timely transfer to a superior hospital are necessary. If the test result is negative, it indicates a low risk of developing PE, reducing the need for excessive clinical examination and intervention.

Rigidifying the β2-α2 Loop in the Mouse Prion Protein Slows down Formation of Misfolded Oligomers.

Transmissible Spongiform Encephalopathies are fatal neurodegenerative diseases caused by the misfolding of the cellular prion protein (PrPC) into its pathological isoform (PrPSc). Efficient transmission of PrPSc occurs within the same species, but a species barrier limits interspecies transmission. While PrP structure is largely conserved among mammals, variations at the β2-α2 loop are observed, and even minor changes in the amino acid sequence of the β2-α2 loop can significantly affect transmission efficiency. The present study shows that the introduction of the elk/deer-specific amino acid substitutions at positions 169 (Ser to Asn) and 173 (Asn to Thr) into the mouse prion protein, which are associated with the structural rigidity of the β2-α2 loop, has a substantial impact on protein dynamics as well as on the misfolding pathways of the protein. Native state hydrogen-deuterium exchange studies coupled with mass spectrometry, show that the rigid loop substitutions stabilize not only the β2-α2 loop but also the C-terminal end of α3, suggesting that molecular interactions between these two segments are strengthened. Moreover, the energy difference between the native state and multiple misfolding-prone partially unfolded forms (PUFs) present at equilibrium, is increased. The decreased accessibility of the PUFs from the native state leads to a slowing down of the misfolding of the protein. The results of this study provide important insights into the early events of conformational conversion of prion protein into β-rich oligomers, and add to the evidence that the β2-α2 loop is a key determinant in prion protein aggregation.

Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders.

The abnormal deposition and intercellular propagation of disease-specific protein play a central role in the pathogenesis of many neurodegenerative disorders. Recent studies share the common observation that the formation of protein oligomers and subsequent pathological filaments is an essential step for the disease. Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) are neurodegenerative diseases characterized by the aggregation of the α-synucleinprotein in neurons and/or in oligodendrocytes (glial cytoplasmic inclusions), neuronal loss, and astrogliosis. A similar mechanism of protein Tau-dependent neurodegeneration is a major feature of tauopathies, represented by Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick's disease (PD). The specific inhibition of the protein misfolding and their interneuronal spreading represents a promising therapeutic strategy against both disease pathology and progression. The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation.

Cpx-signalling in Yersinia pseudotuberculosis modulates Lipid-A remodelling and resistance to last-resort antimicrobials

Antibiotic resistance is a global healthcare crisis. Bacteria are highly adaptable and can rapidly acquire mechanisms of resistance towards conventional antibiotics. The permeability barrier conferred by the Gram-negative bacteria cell envelope constitutes a first line of defence against the action of antibiotics. Exposure to extracytoplasmic stresses can negatively affect cell envelope homoeostasis and this causes localised protein misfolding, compromised envelope integrity and impairs barrier function. The CpxA-CpxR two-component regulatory system has evolved to sense extracytoplasmic stresses and to regulate processes that restore homoeostasis of the cell envelope. Hence, controlled Cpx-signalling assists bacteria in adapting, surviving and proliferating in harsh environments, including exposure to antibiotics. Herein, we determined that an intact Cpx-signalling is key to maintaining the Yersinia pseudotuberculosis resistance to colistin and polymyxin B. The susceptibility displayed by Cpx-signalling defective mutants, correlated with cell-envelope deformity and specific modifications of Lipid-A. In vivo transcriptional analysis and in vitro protein-DNA binding studies demonstrated that these modifications were dependent on the direct regulation of Lipid-A biogenesis and modifications of operons by the active phosphorylated CpxR~P isoform. Altogether, our work defines the regulatory mechanism that enables Cpx-signalling to actively control cell envelope remodelling and the permeability of antibiotics in the clinically relevant enteropathogen Y. pseudotuberculosis.

Heterogeneous folding landscapes and predetermined breaking points within a protein family.

The accurate prediction of protein structures with artificial intelligence has been a spectacular success. Yet, how proteins fold into their native structures inside the cell remains incompletely understood. Of particular interest is to rationalize how proteins interact with the protein homeostasis network, an organism specific set of protein folding and quality control enzymes. Failure of protein homeostasis leads to widespread misfolding and aggregation, and thus neurodegeneration. Here, I present a comparative analysis of the folding of 16 single-domain proteins from the same organism across a protein family, the Saccharomyces cerevisiae small GTPases. Using computational modeling to directly probe protein folding dynamics, this work shows how near identical structures from the same folding environment can exhibit heterogeneous folding landscapes. Remarkably, yeast small GTPases are found to unfold along different pathways either via the N- or C-terminus initiated by structure-encoded predetermined breaking points. Degrons as recognition signals for ubiquitin-dependent degradation were systematically absent from the initial unfolding sites, as if to protect from too rapid degradation upon spontaneous unfolding or before completion of the folding. The presented results highlight a direct coordination of folding pathway and protein homeostasis interaction signals across a protein family. A deeper understanding of the interdependence of proteins with their folding environment will help to rationalize and combat diseases linked to protein misfolding and dysregulation. More generally, this work underlines the importance of understanding protein folding in the cellular context, and highlights valuable constraints towards a systems-level understanding of protein homeostasis.

Ab-Amy 2.0: Predicting light chain amyloidogenic risk of therapeutic antibodies based on antibody language model

Therapeutic antibodies have emerged as a promising treatment option for a wide range of diseases. However, the light chain of antibodies can potentially induce amyloidosis, a condition characterized by protein misfolding and aggregation, posing a significant safety concern. Therefore, it is crucial to assess the amyloidogenic risk of therapeutic antibodies during the early stages of drug development. In this study, we introduce AB-Amy 2.0, a new computational model with enhanced performance for assessing the light chain amyloidogenic risk of therapeutic antibodies. By employing pretrained protein language models (PLMs) embeddings, AB-Amy 2.0 achieves higher accuracy in amyloidogenic risk prediction compared with traditional features offering a crucial tool for early-stage identification of antibodies with low aggregation propensity. The AB-Amy 2.0 was trained on antiBERTy embeddings and utilizes the SVM algorithm, resulting in superior performance metrics. On an independent test dataset, the model achieved high sensitivity, specificity, ACC, MCC and AUC of 93.47%, 89.23%, 91.92%, 0.8261 and 0.9739, respectively. These results highlight the effectiveness and robustness of AB-Amy 2.0 in predicting light chain amyloidogenic risk accurately. To facilitate user-friendly access, we have developed an online web server (http://i.uestc.edu.cn/AB-Amy2) and a command line tool (https://github.com/zzyywww/ABAmy2). These resources enable the broader application of this advanced model and promise to enhance the development of safer therapeutic antibodies.

Copper homeostasis and neurodegenerative diseases.

Copper, one of the most prolific transition metals in the body, required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

“Red Flags”: Case Report of Cardiac Amyloidosis with Significant Coronary Artery Disease

BACKGROUND: Cardiac Amyloidosis is a disorder of protein misfolding and metabolism in which insoluble fibrils are deposited in the myocardial extracellular matrix causing organ dysfunction and eventually death. It can exhibit cardiac signs and symptoms, or it can be identified through screening in patients who exhibit extracardiac symptoms of amyloidosis. As there were no clear clinical signs of cardiac amyloidosis and a biopsy is required to show amyloid deposition, the condition has been historically challenging to diagnose. Thus, a high index of suspicion based on the clinical presentation and the outcomes of the preliminary testing arecrucial to determine the approach to diagnosis. CASE SUMMARY: We outline a case of 75-year-old Filipino male who was admitted due to progressive exertional dyspnea. Cardiac Amyloidosis was considered due to evaluation findings of heart failure with preserved ejection fraction with restrictive type of cardiomyopathy. This was subsequently confirmed through extracardiac fat pad biopsy, echocardiographic strain analysis and Technetium (99mTc) Pyrophosphate (PYP) single photon emission computed tomography scan (SPECT). CONCLUSION: This case report discussed the red flags of clinical manifestations of cardiac amyloidosis and highlighted the use of non-invasive diagnostic modalities to diagnose the disease. Cardiac amyloidosis remains a rare entity and with emerging therapies that have the potential to improve patient outcomes, early diagnosis is really important. Having high index of suspicion based on signs and symptoms can lead to early detection and an increased number of patients being referred for treatment.

Cryo-EM structure of a lysozyme-derived amyloid fibril from hereditary amyloidosis

Systemic ALys amyloidosis is a debilitating protein misfolding disease that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 Å cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. As the conformation of lysozyme in the fibril is otherwise fundamentally different from native lysozyme, our data provide a structural rationale for the need of protein unfolding in the development of systemic ALys amyloidosis.

CSF3RT618I Is Stabilized By Calnexin and Induces Unfolded Protein Response (UPR) and ER-Phagy: A Pro-Survival Pathway for Oncogenic Misfolded CSF3R Proteins in Chronic Neutrophilic Leukemia (CNL)

CSF3RT618I Is Stabilized By Calnexin and Induces Unfolded Protein Response (UPR) and ER-Phagy: A Pro-Survival Pathway for Oncogenic Misfolded CSF3R Proteins in Chronic Neutrophilic Leukemia (CNL)