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The Primary Care Companion For CNS... May 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome
PubMed: 38815266
DOI: 10.4088/PCC.23cr03637 -
Frontiers in Veterinary Science 2024Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)."...
BACKGROUND
Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrP) to a pathogenic isoform, the "scrapie form of prion protein (PrP)." Several studies reported that the shadow of prion protein (Sho), encoded by the shadow of prion protein gene (), is involved in prion disease development by accelerating the conformational conversion of PrP to PrP. Until now, genetic polymorphisms of the gene and the protein structure of Sho related to fragility to prion disease have not been investigated in pheasants, which are a species of poultry.
METHODS
Here, we identified the gene sequence by polymerase chain reaction (PCR) and compared the gene and Sho protein sequences among various prion disease-susceptible and -resistant species to identify the distinctive genetic features of pheasant Sho using Clustal Omega. In addition, we investigated genetic polymorphisms of the gene in pheasants and analyzed genotype, allele, and haplotype frequencies, as well as linkage disequilibrium among the genetic polymorphisms. Furthermore, we used programs, namely Mutpred2, MUpro and AMYCO, to investigate the effect of non-synonymous single nucleotide polymorphisms (SNPs). Finally, the predicted secondary and tertiary structures of Sho proteins from various species were analyzed by Alphafold2.
RESULTS
In the present study, we reported pheasant gene sequences for the first time and identified a total of 14 novel SNPs, including 7 non-synonymous and 4 synonymous SNPs. In addition, the pheasant Sho protein sequence showed 100% identity with the chicken Sho protein sequence. Furthermore, amino acid substitutions were predicted to affect the hydrogen bond distribution in the 3D structure of the pheasant Sho protein.
CONCLUSION
To the best of our knowledge, this is the first report of the genetic and structural features of the pheasant gene.
PubMed: 38812560
DOI: 10.3389/fvets.2024.1399548 -
Cell Reports May 2024Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during...
Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA-binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms aggregate-like puncta in the brains of old killifish and mice. Interestingly, DDX5's prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein's ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.
PubMed: 38810650
DOI: 10.1016/j.celrep.2023.112787 -
Journal of Translational Medicine May 2024Prion diseases are transmissible and fatal neurodegenerative diseases characterized by accumulation of misfolded prion protein isoform (PrP), astrocytosis, microgliosis,...
BACKGROUND
Prion diseases are transmissible and fatal neurodegenerative diseases characterized by accumulation of misfolded prion protein isoform (PrP), astrocytosis, microgliosis, spongiosis, and neurodegeneration. Elevated levels of cell membrane associated PrP protein and inflammatory cytokines hint towards the activation of death receptor (DR) pathway/s in prion diseases. Activation of DRs regulate, either cell survival or apoptosis, autophagy and necroptosis based on the adaptors they interact. Very little is known about the DR pathways activation in prion disease. DR3 and DR5 that are expressed in normal mouse brain were never studied in prion disease, so also their ligands and any DR adaptors. This research gap is notable and investigated in the present study.
METHODS
C57BL/6J mice were infected with Rocky Mountain Laboratory scrapie mouse prion strain. The progression of prion disease was examined by observing morphological and behavioural abnormalities. The levels of PrP isoforms and GFAP were measured as the marker of PrP accumulation and astrocytosis respectively using antibody-based techniques that detect proteins on blot and brain section. The levels of DRs, their glycosylation and ectodomain shedding, and associated factors warrant their examination at protein level, hence western blot analysis was employed in this study.
RESULTS
Prion-infected mice developed motor deficits and neuropathology like PrP accumulation and astrocytosis similar to other prion diseases. Results from this research show higher expression of all DR ligands, TNFR1, Fas and p75NTR but decreased levels DR3 and DR5. The levels of DR adaptor proteins like TRADD and TRAF2 (primarily regulate pro-survival pathways) are reduced. FADD, which primarily regulate cell death, its level remains unchanged. RIPK1, which regulate pro-survival, apoptosis and necroptosis, its expression and proteolysis (inhibits necroptosis but activates apoptosis) are increased.
CONCLUSIONS
The findings from the present study provide evidence towards the involvement of DR3, DR5, DR6, TL1A, TRAIL, TRADD, TRAF2, FADD and RIPK1 for the first time in prion diseases. The knowledge obtained from this research discuss the possible impacts of these 16 differentially expressed DR factors on our understanding towards the multifaceted neuropathology of prion diseases and towards future explorations into potential targeted therapeutic interventions for prion disease specific neuropathology.
Topics: Animals; Prion Diseases; Disease Models, Animal; Mice, Inbred C57BL; Receptors, Death Domain; Signal Transduction; Brain; Mice; PrPSc Proteins; Glial Fibrillary Acidic Protein
PubMed: 38802941
DOI: 10.1186/s12967-024-05121-x -
Viruses May 2024The key postulate of the prion paradigm is that some proteins can take on unconventional conformations and pass these conformations to newly synthesized protein...
The key postulate of the prion paradigm is that some proteins can take on unconventional conformations and pass these conformations to newly synthesized protein molecules with the same primary structure [...].
Topics: Prions; Animals; Humans; Saccharomyces cerevisiae; Prion Diseases; Protein Conformation; Mammals
PubMed: 38793671
DOI: 10.3390/v16050790 -
International Journal of Molecular... May 2024The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the...
The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aβ) and 40 (Aβ) in sCJD ( = 132) and non-prion RPD (np-RPD) ( = 94) patients, and healthy controls (HC) ( = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aβ/Aβ, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Female; Male; Glial Fibrillary Acidic Protein; Aged; Middle Aged; Prognosis; tau Proteins; Biomarkers; Dementia; Amyloid beta-Peptides; Neurofilament Proteins; Disease Progression; 14-3-3 Proteins
PubMed: 38791145
DOI: 10.3390/ijms25105106 -
Brain Sciences Apr 2024Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt-Jakob... (Review)
Review
Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt-Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood-brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions.
PubMed: 38790392
DOI: 10.3390/brainsci14050413 -
Molecular Brain May 2024The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that...
The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.
Topics: Animals; Humans; Mice; alpha-Synuclein; Brain; Cytoplasm; Disease Models, Animal; Green Fluorescent Proteins; Inclusion Bodies; Mice, Transgenic; Multiple System Atrophy; Oligodendroglia; Protein Aggregates; Protein Aggregation, Pathological
PubMed: 38790036
DOI: 10.1186/s13041-024-01104-7 -
Pathogens (Basel, Switzerland) May 2024Prions are proteinaceous pathogens responsible for a variety of devastating diseases in mammals, including scrapie in sheep and goats, chronic wasting disease in...
Prions are proteinaceous pathogens responsible for a variety of devastating diseases in mammals, including scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by their exceptional persistence to common inactivation procedures. This applies to all possible sources of prion contamination as prions may be present in the tissues and biological fluids of infected individuals. Hence, efficient prion inactivation procedures are still being sought to minimize the risk of intra- or inter-species transmission. In the past, photocatalytic treatment has been proven to be capable of efficiently oxidizing and inactivating prions. In the present study, the efficacy of homogeneous photo-Fenton-based photocatalysis as well as heterogeneous photocatalysis with TiO in reducing RML mouse scrapie infectivity was evaluated. Prion inactivation was assessed by means of a bioassay, and the results were confirmed by in vitro experiments. While the prion infectivity of the RML mouse scrapie was reduced after treatment with the photo-Fenton reagent, the heterogeneous photocatalytic treatment of the same prion strain completely eliminated prion infectivity.
PubMed: 38787272
DOI: 10.3390/pathogens13050420 -
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