scholarly journals Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4085
Author(s):  
Antonella Bizzoca ◽  
Martina Caracciolo ◽  
Patrizia Corsi ◽  
Thea Magrone ◽  
Emilio Jirillo ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Mitochondrial Protein ◽  
Growth Control ◽  
Epigallocatechin Gallate ◽  
Neurite Growth ◽  
Mutant Mice ◽  
Protective Effects ◽  
Protein Markers ◽  
Gaa Repeats ◽  
Frataxin Gene

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

Somatic Expansion of the Frataxin Gene GAA Repeats in MDS Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1642-1642
Author(s):  
Drorit Merkel ◽  
H. Joachim Deeg ◽  
Amos Simon ◽  
Ninette Amariglio ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Short Length ◽  
Mrna Levels ◽  
Normal Range ◽  
Heme Synthesis ◽  
Pcr Products ◽  
Gaa Repeats ◽  
The Impact ◽  
Frataxin Gene

Abstract The mitochondria play an important role in both apoptosis and heme synthesis. In patients with Myelodysplastic syndrome (MDS) the marrow is characterized by defective hematopoiesis, increased apoptosis and the presence of iron laden mitochondria. The molecular mechanisms responsible for increased apoptosis remain incompletely understood. Frederic’s ataxia (FRDA), the most common inherited ataxia, is a severe autosomal-recessive disease characterized by neurodegeneration, cardiomyopathy and diabetes, resulting from reduced synthesis of the mitochondrial protein frataxin which is involved in mitochondrial energy production and other cellular functions by providing iron for heme synthesis and iron–sulfur cluster (ISC) assembly and repair, serving as a Fe (II) donor for ferrochelatase. The underlying mutation consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene. Long expansions of a GAA tri-nucleotide in FRDA patients range from 66 to more than 1,700 repeats, whereas the normal range of repeats varies from 7 to 36. Abnormal expansion results in reduced frataxin mRNA levels, leading to reduced function of the respiratory chain. The aim of the present study was to determine if frataxin gene mutations occurred in MDS patients. We analyzed DNA from peripheral blood (PB) of 29 MDS patients and from 22 healthy marrow (BM) donors using repeat-Primed PCR. We also sampled genomic DNA products from buccal smears of the MDS patients. In MDS patients PCR of PB in 9 out of 24 patients (37%) showed short length (2–8 repeats), whereas PB of the remaining 15 patients (62.5%) showed longer PCR products (10–43 repeats, still in the “normal” range for FRDA). The PCR products of the buccal smears from all 14 patient samples were short (2–7 repeats), including those from 9 patients who had longer repeats in PB. In healthy BM donors, PCR of PB detected short length repeats (4–5 repeats) in17 of 20 individuals (85%), whereas 3 samples (15%) had longer PCR products (11–26 repeats). This was statistically significantly different from patients with MDS (P= 0.0014). The results indicate that MDS patients exhibit longer frataxin gene products than healthy individuals in PB, but not in buccal DNA. These data suggest a somatic mutation in the frataxin gene in hematopoetic cells of patients with MDS. Further studies will explore the impact of this mutation on mitochondrial function and on the pathophysiology of MDS.

scholarly journals The Spectrum of Left Ventricular Changes in Friedreich Ataxia—Relation to Age and GAA Repeats in the Frataxin Gene

2012 ◽  
Vol 21 ◽  
pp. S273
Author(s):  
G. Romanelli ◽  
M. Delatycki ◽  
L. Donelan ◽  
R. Hassam ◽  
L. Corben ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Left Ventricular ◽  
Gaa Repeats ◽  
Frataxin Gene

scholarly journals 321. Deletion of Mutated GAA Repeats from the Intron 1 of the Frataxin Gene Using the CRISPR System Restores the Protein Expression in a Friedreich Ataxia Model

2016 ◽  
Vol 24 ◽  
pp. S129
Author(s):  
Dominique L. Ouellet ◽  
Joel Rousseau ◽  
Khadija Cherif ◽  
Catherine Gérard ◽  
Renald Gilbert ◽  
...  
Keyword(s):  
Protein Expression ◽  
Friedreich Ataxia ◽  
Crispr System ◽  
Intron 1 ◽  
Gaa Repeats ◽  
Frataxin Gene

scholarly journals Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

2021 ◽  
Vol 11 (3) ◽  
pp. 325
Author(s):  
Fatima M. Shakova ◽  
Yuliya I. Kirova ◽  
Denis N. Silachev ◽  
Galina A. Romanova ◽  
Sergey G. Morozov
Keyword(s):  
Rat Model ◽  
Nuclear Translocation ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Protein Markers ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacological Agents ◽  
Ischemic Brain ◽  
Neuroprotective Therapy ◽  
Dependent Protein

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain.

scholarly journals Green Tea and Epigallocatechin Gallate (EGCG) for the Management of Nonalcoholic Fatty Liver Diseases (NAFLD): Insights into the Role of Oxidative Stress and Antioxidant Mechanism

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1076
Author(s):  
Guoyi Tang ◽  
Yu Xu ◽  
Cheng Zhang ◽  
Ning Wang ◽  
Huabin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Green Tea ◽  
Liver Diseases ◽  
Randomized Clinical Trials ◽  
Epigallocatechin Gallate ◽  
Protective Effects ◽  
Nonalcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver Diseases ◽  
Underlying Mechanisms

Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.

Frataxin gene point mutations in Italian Friedreich ataxia patients

Neurogenetics ◽  
2007 ◽  
Vol 8 (4) ◽  
pp. 289-299 ◽  
Author(s):  
Cinzia Gellera ◽  
Barbara Castellotti ◽  
Caterina Mariotti ◽  
Rossana Mineri ◽  
Viviana Seveso ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Point Mutations ◽  
Frataxin Gene

scholarly journals Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA.

1997 ◽  
Vol 8 (7) ◽  
pp. 1233-1242 ◽  
Author(s):  
J Nunnari ◽  
W F Marshall ◽  
A Straight ◽  
A Murray ◽  
J W Sedat ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Fluorescence Microscopy ◽  
Fluorescent Dyes ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Dimensional Structure ◽  
Wide Field ◽  
Protein Markers ◽  
Protein Marker ◽  
Mitochondrial Transmission

To gain insight into the process of mitochondrial transmission in yeast, we directly labeled mitochondrial proteins and mitochondrial DNA (mtDNA) and observed their fate after the fusion of two cells. To this end, mitochondrial proteins in haploid cells of opposite mating type were labeled with different fluorescent dyes and observed by fluorescence microscopy after mating of the cells. Parental mitochondrial protein markers rapidly redistributed and colocalized throughout zygotes, indicating that during mating, parental mitochondria fuse and their protein contents intermix, consistent with results previously obtained with a single parentally derived protein marker. Analysis of the three-dimensional structure and dynamics of mitochondria in living cells with wide-field fluorescence microscopy indicated that mitochondria form a single dynamic network, whose continuity is maintained by a balanced frequency of fission and fusion events. Thus, the complete mixing of mitochondrial proteins can be explained by the formation of one continuous mitochondrial compartment after mating. In marked contrast to the mixing of parental mitochondrial proteins after fusion, mtDNA (labeled with the thymidine analogue 5-bromodeoxyuridine) remained distinctly localized to one half of the zygotic cell. This observation provides a direct explanation for the genetically observed nonrandom patterns of mtDNA transmission. We propose that anchoring of mtDNA within the organelle is linked to an active segregation mechanism that ensures accurate inheritance of mtDNA along with the organelle.

Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling

2016 ◽  
Vol 57 (3) ◽  
pp. 349-355 ◽  
Author(s):  
Dorota Hoffman-Zacharska ◽  
Tomasz Mazurczak ◽  
Tomasz Zajkowski ◽  
Renata Tataj ◽  
Paulina Górka-Skoczylas ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Molecular Testing ◽  
Gaa Repeats
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