scholarly journals Prion Proteins Without the Glycophosphatidylinositol Anchor: Potential Biomarkers in Neurodegenerative Diseases

2018 ◽  
Vol 13 ◽  
pp. 117727191875664 ◽  
Author(s):  
Valerija Kovač ◽  
Vladka Čurin Šerbec
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Prion Proteins ◽  
Dual Role ◽  
Neuronal Signaling ◽  
Potential Biomarker ◽  
Potential Biomarkers ◽  
Glycophosphatidylinositol Anchor

Prion protein (PrP) is a biomolecule that is involved in neuronal signaling, myelinization, and the development of neurodegenerative diseases. In the cell, PrP is shed by the ADAM10 protease. This process generates PrP molecules that lack glycophosphatidylinositol anchor, and these molecules incorporate into toxic aggregates and neutralize toxic oligomers. Due to this dual role, these molecules are important biomarkers for neurodegenerative diseases. In this review, we present shed PrP as a potential biomarker, with a focus on PrP226*, which may be the main biomarker for predicting neurodegenerative diseases in humans.

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9006-9006
Author(s):  
Joshua Bauml ◽  
Byoung Chul Cho ◽  
Keunchil Park ◽  
Ki Hyeong Lee ◽  
EUN KYUNG CHO ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Complete Response ◽  
Combination Regimen ◽  
Resistance Mutations ◽  
Tumor Biopsy ◽  
Potential Biomarker ◽  
Treatment Naïve ◽  
Exon 19 Deletion ◽  
Potential Biomarkers

9006 Background: Preliminary efficacy was observed with the combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a 3rd-generation tyrosine kinase inhibitor, in both treatment-naïve and osimertinib (osi)-relapsed patients (pts) with EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). We present updated results of the combination in osi-relapsed pts, including an analysis of potential biomarkers of response. Methods: Pts with EGFR exon 19 deletion or L858R mutation NSCLC, who had progressed on osi without intervening chemotherapy, were enrolled in the combination cohort of the ongoing CHRYSALIS study (NCT02609776). With pre-treatment tumor biopsies and ctDNA collected prospectively, pts received the combination dose of 1050/1400 mg amivantamab + 240 mg lazertinib to assess safety and efficacy in the osi-relapsed population. Response was assessed by investigator per RECIST v1.1. Osi-resistance mutations or amplifications in EGFR/MET identified by next-generation sequencing (NGS) in either ctDNA or tumor biopsy (biomarker-positive [pos]), were evaluated for enriching response. Immunohistochemistry (IHC) staining for EGFR and MET expression was also explored as a potential biomarker for response. Results: Of the 45 osi-relapsed pts, 36% (95% CI, 22–51) had a confirmed response (1 complete response and 15 partial responses [PR]). At a median follow-up of 8.2 mo (1.0–11.8), 20/45 pts (44%) remain on treatment. With 11/16 pts (69%) continuing in response (2.6–9.6+ mo), median duration of response has not been reached (NR). The median progression-free survival (mPFS) was 4.9 mo (95% CI, 3.7–8.3). In total, 44/45 pts were evaluable by ctDNA and 29/45 by tumor NGS. Genetic testing identified 17 biomarker-pos pts, of whom 8 (47%) responded. Of the remaining 28 pts, 8 (29%) responded. Among these 28 pts, 18 had unknown mechanisms of osi-resistance (8 PR) and 10 had non-EGFR/MET mechanisms of resistance identified (none responded). The mPFS (95% CI) for biomarker-pos and remaining pts was 6.7 mo (3.4–NR) and 4.1 mo (1.4–9.5), respectively. Adequate tissue was available for 20 pts to perform IHC testing for EGFR and MET–9/10 (90%) IHC high (combined EGFR+MET H score>400) pts responded to treatment, while 1/10 IHC low pts responded to treatment. Conclusions: Treatment with the combination of amivantamab and lazertinib yielded responses in 36% of chemotherapy-naïve pts who progressed on osi. Among these pts, genetic EGFR and MET-based biomarkers of resistance identified a subgroup of pts more likely to respond to amivantamab and lazertinib, although additional pts lacking identified resistance markers also responded. An IHC-based approach may identify pts most likely to benefit from the combination regimen, but further investigation is warranted. Clinical trial information: NCT02609776.

COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers

2019 ◽  
Vol 19 (11) ◽  
pp. 1007-1018 ◽  
Author(s):  
Katrin Thüne ◽  
Matthias Schmitz ◽  
Anna Villar-Piqué ◽  
Hermann Clemens Altmeppen ◽  
Markus Schlomm ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Potential Biomarkers

scholarly journals Metabolomic Biomarkers of Multiple Sclerosis: A Systematic Review

2020 ◽  
Vol 7 ◽  
Author(s):  
Lachlan Porter ◽  
Alireza Shoushtarizadeh ◽  
George A. Jelinek ◽  
Chelsea R. Brown ◽  
Chai K. Lim ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Magnetic Resonance ◽  
High Throughput Sequencing ◽  
Cochrane Library ◽  
Clinical Criteria ◽  
Diagnosis And Prognosis ◽  
Csf Analysis ◽  
Potential Biomarker ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Biomarkers

BackgroundMagnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, and the McDonald’s clinical criteria are currently utilized tools in diagnosing multiple sclerosis. However, a more conclusive, consistent, and efficient way of diagnosing multiple sclerosis (MS) is yet to be discovered. A potential biomarker, discovered using advances in high-throughput sequencing such as nuclear magnetic resonance (NMR) spectroscopy and other “Omics”-based techniques, may make diagnosis and prognosis more reliable resulting in a more personalized and targeted treatment regime and improved outcomes. The aim of this review was to systematically search the literature for potential biomarkers from any bodily fluid that could consistently and accurately diagnose MS and/or indicate disease progression.MethodsA systematic literature review of EMBASE, PubMed (MEDLINE), The Cochrane Library, and CINAHL databases produced over a thousand potential studies. Inclusion criteria stated studies with potential biomarker outcomes for people with MS were to be included in the review. Studies were limited to those with human participants who had a clinically defined diagnosis of MS and published in English, with no limit placed on date of publication or the type of bodily fluid sampled.ResultsA total of 1,805 studies were recorded from the literature search. A total of 1,760 studies were removed based on their abstract, with a further 18 removed after considering the full text. A total of 30 studies were considered relevant and had their data retrieved and analyzed. Due to the heterogeneity of focus and results from the refined studies, a narrative synthesis was favored.ConclusionSeveral promising candidate biomarkers suitable for clinical application in MS have been studied. It is recommended follow-up studies with larger sample sizes be completed on several potential biomarkers.

Plasma total prion protein as a potential biomarker for neurodegenerative dementia: diagnostic accuracy in the spectrum of prion diseases

2019 ◽  
Vol 46 (3) ◽  
pp. 240-254 ◽  
Author(s):  
F. Llorens ◽  
A. Villar‐Piqué ◽  
M. Schmitz ◽  
D. Diaz‐Lucena ◽  
M. Wohlhage ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Prion Protein ◽  
Prion Diseases ◽  
Potential Biomarker ◽  
Neurodegenerative Dementia

scholarly journals Disturbances in Metabolic Pathways and the Identification of a Potential Biomarker Panel for Early Cartilage Degeneration in a Rabbit Anterior Cruciate Ligament Transection Model

Cartilage ◽  
2020 ◽  
pp. 194760352092143
Author(s):  
Yiwen Hu ◽  
Qian Wu ◽  
Yang Qiao ◽  
Peng Zhang ◽  
Wentao Dai ◽  
...  
Keyword(s):  
Anterior Cruciate Ligament ◽  
Cruciate Ligament ◽  
Pearson Correlation ◽  
Rabbit Model ◽  
Cartilage Degeneration ◽  
Anterior Cruciate Ligament Transection ◽  
Sham Surgery ◽  
Potential Biomarker ◽  
Anterior Cruciate ◽  
Potential Biomarkers

Objective This study aimed to assess the association between synovial fluid (SF) metabolites and magnetic resonance imaging (MRI) measurements of cartilage biochemical composition to identify potential SF biomarkers for detecting the early onset of cartilage degeneration in a rabbit model. Methods Both knees of 12 New Zealand White rabbits were used. The anterior cruciate ligament transection (ACLT) model was performed on right knees, and the sham surgery on left knees. MRI UTE-T2* scanning and SF sample collection were performed on ACLT knees at 4 and 8 weeks postsurgery and on sham surgery knees at 4 weeks postsurgery. Ultra-performance liquid chromatography–mass spectrometry and multivariate statistical analysis were used to distinguish samples in three groups. Pathway and receiver operating characteristic analyses were utilized to identify potential metabolite biomarkers. Results There were 12 knees in sham surgery models, 11 in ACLT models at 4 weeks postsurgery, and 10 in ACLT models at 8 weeks postsurgery. UTE-T2* values for the lateral tibia cartilage showed significant decreases over the study period. Levels of 103 identified metabolites in SF were markedly different among three groups. Furthermore, 24 metabolites were inversely correlated with UTE-T2* values of the lateral tibia cartilage, while hippuric acid was positively correlated with UTE-T2* values of the lateral tibia cartilage. Among 25 potential markers, N1-acetylspermidine, 2-amino-1,3,4-octadecanetriol, l-phenylalanine, 5-hydroxy-l-tryptophan, and l-tryptophan were identified as potential biomarkers with high area under the curve values and Pearson correlation coefficients. Conclusion Five differential metabolites in SF were found as potential biomarkers for the early detection of cartilage degeneration in the rabbit ACLT model.

scholarly journals Prion Protein Repeat Expansion Results in Increased Aggregation and Reveals Phenotypic Variability

2007 ◽  
Vol 27 (15) ◽  
pp. 5445-5455 ◽  
Author(s):  
Elizabeth M. H. Tank ◽  
David A. Harris ◽  
Amar A. Desai ◽  
Heather L. True
Keyword(s):  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Proteins ◽  
Prion Diseases ◽  
Phenotypic Variability ◽  
Conformational Flexibility ◽  
Repeat Expansion ◽  
Chimeric Proteins ◽  
Prion Conversion ◽  
Aggregate Structures

ABSTRACT Mammalian prion diseases are fatal neurodegenerative disorders dependent on the prion protein PrP. Expansion of the oligopeptide repeats (ORE) found in PrP is associated with inherited prion diseases. Patients with ORE frequently harbor PrP aggregates, but other factors may contribute to pathology, as they often present with unexplained phenotypic variability. We created chimeric yeast-mammalian prion proteins to examine the influence of the PrP ORE on prion properties in yeast. Remarkably, all chimeric proteins maintained prion characteristics. The largest repeat expansion chimera displayed a higher propensity to maintain a self-propagating aggregated state. Strikingly, the repeat expansion conferred increased conformational flexibility, as observed by enhanced phenotypic variation. Furthermore, the repeat expansion chimera displayed an increased rate of prion conversion, but only in the presence of another aggregate, the [RNQ +] prion. We suggest that the PrP ORE increases the conformational flexibility of the prion protein, thereby enhancing the formation of multiple distinct aggregate structures and allowing more frequent prion conversion. Both of these characteristics may contribute to the phenotypic variability associated with PrP repeat expansion diseases.

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