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Cells May 2024Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing... (Review)
Review
Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. The brain has a complex network of neurons and glial cells whose crosstalk is critical for function and homeostasis. Although it is established that prion infection of neurons is necessary for clinical disease to occur, debate remains in the field as to the role played by glial cells, namely astrocytes and microglia, and whether these cells are beneficial to the host or further accelerate disease. Here, we review the current literature assessing the complex morphologies of astrocytes and microglia, and the crosstalk between these two cell types, in the prion-infected brain.
Topics: Humans; Prion Diseases; Animals; Neuroglia; Astrocytes; Brain; Neurobiology; Microglia; Neurons; Neuropathology; Prions
PubMed: 38786054
DOI: 10.3390/cells13100832 -
Diseases (Basel, Switzerland) Apr 2024Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered....
Role of B Cells beyond Antibodies in HBV-Induced Oncogenesis: Fulminant Cancer in Common Variable Immunodeficiency-Clinical and Immunotransplant Implications with a Review of the Literature.
Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 10 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.
PubMed: 38785735
DOI: 10.3390/diseases12050080 -
JPMA. the Journal of the Pakistan... May 2024
Topics: Laryngoscopes; Creutzfeldt-Jakob Syndrome; Laryngoscopy; Disposable Equipment; Equipment Reuse; Humans
PubMed: 38783464
DOI: 10.47391/JPMA.10996 -
Emerging Infectious Diseases Jun 2024Chronic wasting disease (CWD) is a cervid prion disease with unknown zoonotic potential that might pose a risk to humans who are exposed. To assess the potential of CWD...
Chronic wasting disease (CWD) is a cervid prion disease with unknown zoonotic potential that might pose a risk to humans who are exposed. To assess the potential of CWD to infect human neural tissue, we used human cerebral organoids with 2 different prion genotypes, 1 of which has previously been associated with susceptibility to zoonotic prion disease. We exposed organoids from both genotypes to high concentrations of CWD inocula from 3 different sources for 7 days, then screened for infection periodically for up to 180 days. No de novo CWD propagation or deposition of protease-resistant forms of human prions was evident in CWD-exposed organoids. Some persistence of the original inoculum was detected, which was equivalent in prion gene knockout organoids and thus not attributable to human prion propagation. Overall, the unsuccessful propagation of CWD in cerebral organoids supports a strong species barrier to transmission of CWD prions to humans.
Topics: Wasting Disease, Chronic; Humans; Organoids; Prions; Animals; Brain; Genotype
PubMed: 38781931
DOI: 10.3201/eid3006.231568 -
Proceedings of the National Academy of... May 2024The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions...
The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer's disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.
Topics: tau Proteins; Lysosomes; Cytosol; Animals; Astrocytes; Neurons; Humans; Intracellular Membranes; Endocytosis; Mice; Cells, Cultured
PubMed: 38781206
DOI: 10.1073/pnas.2315690121 -
Medical Image Analysis Jul 2024Mounting evidence shows that Alzheimer's disease (AD) is characterized by the propagation of tau aggregates throughout the brain in a prion-like manner. Since current...
Mounting evidence shows that Alzheimer's disease (AD) is characterized by the propagation of tau aggregates throughout the brain in a prion-like manner. Since current pathology imaging technologies only provide a spatial mapping of tau accumulation, computational modeling becomes indispensable in analyzing the spatiotemporal propagation patterns of widespread tau aggregates from the longitudinal data. However, current state-of-the-art works focus on the longitudinal change of focal patterns, lacking a system-level understanding of the tau propagation mechanism that can explain and forecast the cascade of tau accumulation. To address this limitation, we conceptualize that the intercellular spreading of tau pathology forms a dynamic system where each node (brain region) is ubiquitously wired with other nodes while interacting with the build-up of pathological burdens. In this context, we formulate the biological process of tau spreading in a principled potential energy transport model (constrained by brain network topology), which allows us to develop an explainable neural network for uncovering the spatiotemporal dynamics of tau propagation from the longitudinal tau-PET scans. Specifically, we first translate the transport equation into a GNN (graph neural network) backbone, where the spreading flows are essentially driven by the potential energy of tau accumulation at each node. Conventional GNNs employ a l-norm graph smoothness prior, resulting in nearly equal potential energies across nodes, leading to vanishing flows. Following this clue, we introduce the total variation (TV) into the graph transport model, where the nature of system's Euler-Lagrange equations is to maximize the spreading flow while minimizing the overall potential energy. On top of this min-max optimization scenario, we design a generative adversarial network (GAN-like) to characterize the TV-based spreading flow of tau aggregates, coined TauFlowNet. We evaluate our TauFlowNet on ADNI and OASIS datasets in terms of the prediction accuracy of future tau accumulation and explore the propagation mechanism of tau aggregates as the disease progresses. Compared to the current counterpart methods, our physics-informed deep model yields more accurate and interpretable results, demonstrating great potential in discovering novel neurobiological mechanisms through the lens of machine learning.
Topics: Humans; Alzheimer Disease; tau Proteins; Positron-Emission Tomography; Neural Networks, Computer; Brain
PubMed: 38776842
DOI: 10.1016/j.media.2024.103210 -
Brain : a Journal of Neurology May 2024
PubMed: 38771700
DOI: 10.1093/brain/awae151 -
Acta Neuropathologica May 2024
Topics: Humans; Mutation; Prions; Male; Prion Diseases; Brain; Female
PubMed: 38767731
DOI: 10.1007/s00401-024-02738-6 -
Frontiers in Neurology 2024Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported...
BACKGROUND
Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD.
OBJECTIVE
This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with or mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies.
METHODS
We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with mutations, two patients with mutations, 16 patients with mutations, 14 patients with mutations, five patients with mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy.
RESULTS
P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with , , or mutations but not in those with or mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and and mutation patients revealed prion-like activity.
CONCLUSION
P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.
PubMed: 38751879
DOI: 10.3389/fneur.2024.1404492 -
Veterinary Research May 2024The first case of CWD in a Norwegian red deer was detected by a routine ELISA test and confirmed by western blotting and immunohistochemistry in the brain stem of the...
The first case of CWD in a Norwegian red deer was detected by a routine ELISA test and confirmed by western blotting and immunohistochemistry in the brain stem of the animal. Two different western blotting tests were conducted independently in two different laboratories, showing that the red deer glycoprofile was different from the Norwegian CWD reindeer and CWD moose and from North American CWD. The isolate showed nevertheless features similar to the classical BSE (BSE-C) strain. Furthermore, BSE-C could not be excluded based on the PrP immunohistochemistry staining in the brainstem and the absence of detectable PrP in the lymphoid tissues. Because of the known ability of BSE-C to cross species barriers as well as its zoonotic potential, the CWD red deer isolate was submitted to the EURL Strain Typing Expert Group (STEG) as a BSE-C suspect for further investigation. In addition, different strain typing in vivo and in vitro strategies aiming at identifying the BSE-C strain in the red deer isolate were performed independently in three research groups and BSE-C was not found in it. These results suggest that the Norwegian CWD red deer case was infected with a previously unknown CWD type and further investigation is needed to determine the characteristics of this potential new CWD strain.
Topics: Animals; Deer; Encephalopathy, Bovine Spongiform; Norway; Wasting Disease, Chronic; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Prions; Cattle; Immunohistochemistry; PrPSc Proteins
PubMed: 38750594
DOI: 10.1186/s13567-024-01320-y