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Neurology Jul 2024
Topics: Humans; Biomarkers; Prion Diseases; Predictive Value of Tests; Prions
PubMed: 38896818
DOI: 10.1212/WNL.0000000000209580 -
Neurology Jul 2024To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion.
OBJECTIVES
To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion.
METHODS
This single-center longitudinal cohort study has followed known carriers of pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF.
RESULTS
Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints.
DISCUSSION
CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.
CLINICAL TRIALS REGISTRATION
ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.
Topics: Humans; Female; Male; Middle Aged; Biomarkers; Prion Proteins; Prion Diseases; Longitudinal Studies; Adult; tau Proteins; Neurofilament Proteins; Heterozygote; Glial Fibrillary Acidic Protein; Disease Progression; alpha-Synuclein
PubMed: 38896810
DOI: 10.1212/WNL.0000000000209506 -
Archives of Microbiology Jun 2024Prion-like proteins (PrLPs) have emerged as beneficial molecules with implications in adaptive responses. These proteins possess a conserved prion-like domain (PrLD)...
Prion-like proteins (PrLPs) have emerged as beneficial molecules with implications in adaptive responses. These proteins possess a conserved prion-like domain (PrLD) which is an intrinsically disordered region capable of adopting different conformations upon perceiving external stimuli. Owing to changes in protein conformation, functional characteristics of proteins harboring PrLDs get altered thereby, providing a unique mode of protein-based regulation. Since PrLPs are ubiquitous in nature and involved in diverse functions, through this study, we aim to explore the role of such domains in yet another important physiological process viz. plant-microbe interactions to get insights into the mechanisms dictating cross-kingdom interactions. We have evaluated the presence and functions of PrLPs in 18 different plant-associated fungi of agricultural importance to unravel their role in plant-microbe interactions. Of the 241,997 proteins scanned, 3,820 (~ 1.6%) were identified as putative PrLPs with pathogenic fungi showing significantly higher PrLP density than their beneficial counterparts. Further, through GO enrichment analysis, we could predict several PrLPs from pathogenic fungi to be involved in virulence and formation of stress granules. Notably, PrLPs involved in (retro)transposition were observed exclusively in pathogenic fungi. We even analyzed publicly available data for the expression alterations of fungal PrLPs upon their interaction with their respective hosts which revealed perturbation in the levels of some PrLP-encoding genes during interactions with plants. Overall, our work sheds light into the probable role of prion-like candidates in plant-fungi interaction, particularly in context of pathogenesis, paving way for more focused studies for validating their role.
Topics: Fungal Proteins; Plants; Fungi; Computer Simulation; Plant Diseases; Prion Proteins; Prions; Virulence; Host-Pathogen Interactions
PubMed: 38896139
DOI: 10.1007/s00203-024-04040-1 -
BioRxiv : the Preprint Server For... Jun 2024RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is...
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic FTLD. Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
PubMed: 38895337
DOI: 10.1101/2024.06.03.593639 -
Animals : An Open Access Journal From... May 2024Prion diseases are fatal neurodegenerative disorders characterized by an accumulation of misfolded prion protein (PrP) in brain tissues. The shadow of prion protein...
Prion diseases are fatal neurodegenerative disorders characterized by an accumulation of misfolded prion protein (PrP) in brain tissues. The shadow of prion protein (Sho) encoded by the shadow of prion protein gene () is involved in prion disease progress. The interaction between Sho and PrP accelerates the PrP conversion rate while the gene polymorphisms have been associated with prion disease susceptibility in several species. Until now, the gene has not been investigated in ducks. We identified the duck gene sequence and investigated the genetic polymorphisms of 184 Pekin ducks. We compared the duck nucleotide sequence and the duck Sho protein amino acid sequence with those of several other species. Finally, we predicted the duck Sho protein structure and the effects of non-synonymous single nucleotide polymorphisms (SNPs) using computational programs. We were the first to report the Pekin duck gene sequence. The duck Sho protein sequence showed 100% identity compared with the chicken Sho protein sequence. We found 27 novel SNPs in the duck gene. Four amino acid substitutions were predicted to affect the hydrogen bond distribution in the duck Sho protein structure. Although MutPred2 and SNPs&GO predicted that all non-synonymous polymorphisms were neutral or benign, SIFT predicted that four variants, A22T, G49D, A68T, and M105I, were deleterious. To the best of our knowledge, this is the first report about the genetic and structural characteristics of the duck gene.
PubMed: 38891635
DOI: 10.3390/ani14111588 -
Foods (Basel, Switzerland) Jun 2024Curcumin, a hydrophobic polyphenol extracted from the rhizome of , is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's... (Review)
Review
Curcumin, a hydrophobic polyphenol extracted from the rhizome of , is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.
PubMed: 38891002
DOI: 10.3390/foods13111774 -
Nature Medicine Jun 2024Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show...
Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.
Topics: Humans; Amyotrophic Lateral Sclerosis; tau Proteins; Extracellular Vesicles; Frontotemporal Dementia; Biomarkers; DNA-Binding Proteins; Female; Male; Aged; Middle Aged; Supranuclear Palsy, Progressive; Protein Isoforms
PubMed: 38890531
DOI: 10.1038/s41591-024-02937-4 -
Japanese Journal of Radiology Jun 2024The findings of brain perfusion single-photon emission computed tomography (SPECT), which detects abnormalities often before changes manifest in morphological imaging,... (Review)
Review
The findings of brain perfusion single-photon emission computed tomography (SPECT), which detects abnormalities often before changes manifest in morphological imaging, mainly reflect neurodegeneration and contribute to dementia evaluation. A major shift is about to occur in dementia practice to the approach of diagnosing based on biomarkers and treating with disease-modifying drugs. Accordingly, brain perfusion SPECT will be required to serve as a biomarker of neurodegeneration. Hypoperfusion in Alzheimer's disease (AD) is typically seen in the posterior cingulate cortex and precuneus early in the disease, followed by the temporoparietal cortices. On the other hand, atypical presentations of AD such as the posterior variant, logopenic variant, frontal variant, and corticobasal syndrome exhibit hypoperfusion in areas related to symptoms. Additionally, hypoperfusion especially in the precuneus and parietal association cortex can serve as a predictor of progression from mild cognitive impairment to AD. In dementia with Lewy bodies (DLB), the differentiating feature is the presence of hypoperfusion in the occipital lobes in addition to that observed in AD. Hypoperfusion of the occipital lobe is not a remarkable finding, as it is assumed to reflect functional loss due to impairment of the cholinergic and dopaminergic systems rather than degeneration per se. Moreover, the cingulate island sign reflects the degree of AD pathology comorbid in DLB. Frontotemporal dementia is characterized by regional hypoperfusion according to the three clinical types, and the background pathology is diverse. Idiopathic normal pressure hydrocephalus shows apparent hypoperfusion around the Sylvian fissure and corpus callosum and apparent hyperperfusion in high-convexity areas. The cortex or striatum with diffusion restriction on magnetic resonance imaging in prion diseases reflects spongiform degeneration and brain perfusion SPECT reveals hypoperfusion in the same areas. Brain perfusion SPECT findings in dementia should be carefully interpreted considering background pathology.
PubMed: 38888851
DOI: 10.1007/s11604-024-01612-5 -
Advanced Science (Weinheim,... Jun 2024The mechanism research of skin wrinkles, conducted on volunteers underwent high-intensity desk work and mice subjected to partial sleep deprivation, revealed a...
The mechanism research of skin wrinkles, conducted on volunteers underwent high-intensity desk work and mice subjected to partial sleep deprivation, revealed a significant reduction in dermal thickness associated with the presence of wrinkles. This can be attributed to the activation of facial nerves in a state of hysteria due to an abnormally elevated interaction between SNAP25 and RAB3A proteins involved in the synaptic vesicle cycle (SVC). Facilitated by AI-assisted structural design, a refined peptide called RSI is developed to modulate this interaction and normalize SVC. Drawing inspiration from prions, which possess the ability to protect themselves against proteolysis and invade neighboring nerve cells through macropinocytosis, RSI is engineered to demonstrate a GSH-responsive reversible self-assembly into a prion-like supermolecule (RSI). RSI showcases protease resistance, micropinocytosis-dependent cellular internalization, and low adhesion with constituent molecules in the cuticle, thereby endowing it with the transdermic absorption and subsequent biofunction in redressing the frenzied SVC. As a facial mud mask, it effectively reduces periorbital and perinasal wrinkles in the human face. Collectively, RSI not only presents a clinical potential as an anti-wrinkle prion-like supermolecule, but also exemplifies a reproducible instance of bionic strategy-guided drug development that bestows transdermal ability upon the pharmaceutical molecule.
PubMed: 38888508
DOI: 10.1002/advs.202308764 -
The European Journal of Neuroscience Jun 2024Mouse neuronal CAD 5 cell line effectively propagates various strains of prions. Previously, we have shown that it can also be differentiated into the cells...
Mouse neuronal CAD 5 cell line effectively propagates various strains of prions. Previously, we have shown that it can also be differentiated into the cells morphologically resembling neurons. Here, we demonstrate that CAD 5 cells chronically infected with prions undergo differentiation under the same conditions. To make our model more realistic, we triggered the differentiation in the 3D culture created by gentle rocking of CAD 5 cell suspension. Spheroids formed within 1 week and were fully developed in less than 3 weeks of culture. The mature spheroids had a median size of ~300 μm and could be cultured for up to 12 weeks. Increased expression of differentiation markers GAP 43, tyrosine hydroxylase, β-III-tubulin and SNAP 25 supported the differentiated status of the spheroid cells. The majority of them were found in the G0/G1 phase of the cell cycle, which is typical for differentiated cells. Moreover, half of the PrP on the cell membrane was N-terminally truncated, similarly as in differentiated CAD 5 adherent cells. Finally, we demonstrated that spheroids could be created from prion-infected CAD 5 cells. The presence of prions was verified by immunohistochemistry, western blot and seed amplification assay. We also confirmed that the spheroids can be infected with the prions de novo. Our 3D culture model of differentiated CAD 5 cells is low cost, easy to produce and cultivable for weeks. We foresee its possible use in the testing of anti-prion compounds and future studies of prion formation dynamics.
PubMed: 38887188
DOI: 10.1111/ejn.16444