scholarly journals Antisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy For Tauopathies

2014 ◽  
Vol 3 ◽  
pp. e180 ◽  
Author(s):  
Reeteka Sud ◽  
Evan T Geller ◽  
Gerard D Schellenberg
Keyword(s):  
Protein Expression ◽  
Tau Protein ◽  
Exon Skipping

scholarly journals Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy

2021 ◽  
pp. 1-20
Author(s):  
James S. Novak ◽  
Rita Spathis ◽  
Utkarsh J. Dang ◽  
Alyson A. Fiorillo ◽  
Ravi Hindupur ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Expression ◽  
Protein Turnover ◽  
Isotope Labeling ◽  
Exon Skipping ◽  
Mdx Mice ◽  
Wild Type ◽  
Gene Correction ◽  
Dystrophin Protein

Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies –Eteplirsen, Golodirsen, Viltolarsen, and Casimersen –for Duchenne Muscular Dystrophy (DMD). However, these treatments have only demonstrated variable and largely sub-therapeutic levels of restored dystrophin protein in DMD patients, limiting their clinical impact. To better understand variable protein expression and the behavior of truncated dystrophin protein in vivo, we assessed turnover dynamics of restored dystrophin and dystroglycan complex (DGC) proteins in mdx mice after exon skipping therapy, compared to those dynamics in wild type mice, using a targeted, highly-reproducible and sensitive, in vivo stable isotope labeling mass spectrometry approach in multiple muscle tissues. Through statistical modeling, we found that restored dystrophin protein exhibited altered stability and slower turnover in treated mdx muscle compared with that in wild type muscle (∼44 d vs. ∼24 d, respectively). Assessment of mRNA transcript stability (quantitative real-time PCR, droplet digital PCR) and dystrophin protein expression (capillary gel electrophoresis, immunofluorescence) support our dystrophin protein turnover measurements and modeling. Further, we assessed pathology-induced muscle fiber turnover through bromodeoxyuridine (BrdU) labeling to model dystrophin and DGC protein turnover in the context persistent fiber degeneration. Our findings reveal sequestration of restored dystrophin protein after exon skipping therapy in mdx muscle leading to a significant extension of its half-life compared to the dynamics of full-length dystrophin in normal muscle. In contrast, DGC proteins show constant turnover attributable to myofiber degeneration and dysregulation of the extracellular matrix (ECM) in dystrophic muscle. Based on our results, we demonstrate the use of targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of disease and propose its use to optimize alternative gene correction strategies in development for DMD.

Flavonoids from Scutellaria baicalensis Georgi Stems and Leaves Regulate the Brain Tau Hyperphosphorylation at M|ultiple Sites Induced by Composited Aβ in Rats

2021 ◽  
Vol 20 ◽  
Author(s):  
Yazhen Shang ◽  
Shengkai Ding
Keyword(s):  
Cerebral Cortex ◽  
Protein Expression ◽  
Tau Protein ◽  
Drug Group ◽  
Scutellaria Baicalensis ◽  
Intracerebroventricular Injection ◽  
Model Group ◽  
Expression Levels ◽  
Scutellaria Baicalensis Georgi ◽  
Stems And Leaves

Background: Neurofibrillary tangles (NFTs), formed by hyperphosphorylation of Tau protein in Alzheimer's disease (AD) are the main pathomechanisms of neuronal degeneration, which can be used as a sign of brain disorder. It is positively correlated with the degree of cognitive impairment in AD. Objective: The objective of this study is to investigate the effect of Scutellaria baicalensis Georgi stems and leaves flavonoids (SSF) on the hyperphosphorylated expression levels at multiple sites of Tau protein induced by β-amyloid protein 25-35 (Aβ25-35) in combined with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1 (RHTGF-β1) (composited Aβ) in rats. Methods: The model of rats for AD was established by intracerebroventricular injection of Aβ25-35 and AlCl3 combined with RHTGF-β1. On day 45 after the operation, the Morris water maze was used to screen the rats’ memory impairment model for AD. The successful model rats were randomly divided into the model group and three-dose of drug group. The drug group rats were daily and orally SSF administrated for 38 days. Western blotting was used to detect the protein expression of P-Tau (Thr181), P-Tau (Thr217), P-Tau (Thr231), P-Tau (Ser199), P-Tau (Ser235), P-Tau (Ser396) and P-Tau (Ser404) in the hippocampus and cerebral cortex of rats. Results: Compared with the sham group, the protein expression of P-Tau (Thr181), P-Tau (Thr217), P-Tau (Thr231), P-Tau (Ser199), P-Tau (Ser235), P-Tau (Ser396) and P-Tau (Ser404) was significantly increased in the hippocampus and cerebral cortex in the model group (P < 0.01). However, the three doses of 35, 70 and 140 mg/kg SSF regulated the expression of phosphorylated Tau protein at the above sites to varying degrees in the hippocampus and cerebral cortex (P < 0.01) induced by composited Aβ. Conclusion: SSF can significantly reduce the protein expression levels of P-Tau (Thr181), P-Tau (Thr217), P-Tau (Thr231), P-Tau (Ser199), P-Tau (Ser235), P-Tau (Ser396) and P-Tau (Ser404) in rats’ brain induced by the intracerebroventricular injection of composited Aβ. These results demonstrated that the neuro-protection and the impaired memory improvement of SSF were due to the inhibition for the hyperphosphorylation of Tau protein at multiple sites.

Relationship Between Gastric Cancer Tau Protein Expression and Paclitaxel Sensitivity

2013 ◽  
Vol 19 (3) ◽  
pp. 429-435 ◽  
Author(s):  
Qiong Wang ◽  
Nanyao Wang ◽  
Guoyi Shao ◽  
Jianzhong Qian ◽  
Dong Shen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Protein Expression ◽  
Tau Protein

scholarly journals The Effect of Synonymous Single-Nucleotide Polymorphisms on an Atypical Cystic Fibrosis Clinical Presentation

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Giovana Bampi ◽  
Anabela Ramalho ◽  
Leonardo Santos ◽  
Johannes Wagner ◽  
Lieven Dupont ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Single Nucleotide Polymorphisms ◽  
Protein Expression ◽  
Protein Function ◽  
Low Frequency ◽  
Exon Skipping ◽  
Cftr Gene ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Exon 11

Synonymous single nucleotide polymorphisms (sSNPs), which change a nucleotide, but not the encoded amino acid, are perceived as neutral to protein function and thus, classified as benign. We report a patient who was diagnosed with cystic fibrosis (CF) at an advanced age and presented very mild CF symptoms. The sequencing of the whole cystic fibrosis transmembrane conductance regulator (CFTR) gene locus revealed that the patient lacks known CF-causing mutations. We found a homozygous sSNP (c.1584G>A) at the end of exon 11 in the CFTR gene. Using sensitive molecular methods, we report that the c.1584G>A sSNP causes cognate exon skipping and retention of a sequence from the downstream intron, both of which, however, occur at a relatively low frequency. In addition, we found two other sSNPs (c.2562T>G (p.Thr854=) and c.4389G>A (p.Gln1463=)), for which the patient is also homozygous. These two sSNPs stabilize the CFTR protein expression, compensating, at least in part, for the c.1584G>A-triggered inefficient splicing. Our data highlight the importance of considering sSNPs when assessing the effect(s) of complex CFTR alleles. sSNPs may epistatically modulate mRNA and protein expression levels and consequently influence disease phenotype and progression.

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