The final approach involves creating transgenic mice with a GAA-expanded version of the human frataxin gene. (wikipedia.org)
PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. (bvsalud.org)
Mitochondrial protein3
Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. (wikipedia.org)
TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. (frontiersin.org)
TTC triplet repeat expansion in an intron of the nuclear FXN gene, which encodes the essential mitochondrial protein frataxin ( 1 ). (frontiersin.org)
Intron6
The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in bacteria and Human cells or both. (wikipedia.org)
Although nearly all organisms express a frataxin homologue, the GAA repeat in intron 1 only exists in humans and other primates, so the mutation that causes FDRA can't occur naturally in other animals. (wikipedia.org)
Another approach involves inserting a GAA expansion into the first intron of the mouse FXN gene, which should inhibit frataxin production, just like in humans. (wikipedia.org)
TTC repeats ( 6 , 7 , 15 ), as well as with reduced histone acetylation and increased histone trimethylation at the FXN promoter ( 6 , 8 ), and in intron 1 adjacent to the repeats ( 5 - 7 ). (frontiersin.org)
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. (bvsalud.org)
FRDA8
Overall, this leads to a decrease in frataxin mRNA synthesis and a decrease (but not absence) in frataxin protein in people with FRDA. (wikipedia.org)
A subset of FRDA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome. (wikipedia.org)
FRDA patients' peripheral tissues typically have less than 10% of the frataxin levels exhibited by unaffected people. (wikipedia.org)
Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. (frontiersin.org)
The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. (bvsalud.org)
These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. (bvsalud.org)
Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. (bvsalud.org)
MRNA2
It is located in the mitochondrion and Frataxin mRNA is mostly expressed in tissues with a high metabolic rate. (wikipedia.org)
Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). (wikipedia.org)
Assembly of iron-sul2
The function of frataxin is not clear but it is involved in assembly of iron-sulfur clusters. (wikipedia.org)
The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. (wikipedia.org)
Encodes1
Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin. (wikipedia.org)
Protein1
Frataxin is a protein that in humans is encoded by the FXN gene. (wikipedia.org)
Knockout1
Mice that are homozygous for this modified gene are called KIKI (knock-in knock-in), and the compound heterozygotes formed by crossing KIKI mice with frataxin knockout mice are called KIKO (knock-in knock-out). (wikipedia.org)
Transcription1
TTC expansion mutation is to reduce expression of frataxin at the level of transcription ( 3 ), through the formation of heterochromatin and subsequent gene silencing ( 4 - 8 ). (frontiersin.org)
Allele1
In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels. (wikipedia.org)
Mild1
However, even KIKO mice still express 25-36% of the normal frataxin level, and show very mild symptoms. (wikipedia.org)
Levels2
Lower levels of frataxin result in earlier disease onset and faster progression. (wikipedia.org)
Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. (regenerativemedicine.net)
Mice3
One approach is to silence frataxin expression in just one specific tissue type of interest: the heart (mice modified this way are called MCK), all neurons (NSE), or just the spinal cord and cerebellum (PRP). (wikipedia.org)
Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. (bvsalud.org)
In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. (bvsalud.org)
Expression2
Reduced expression of frataxin is the cause of Friedreich's ataxia. (wikipedia.org)
This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression. (wikipedia.org)
Parallel1
X-ray crystallography has shown that human frataxin consists of a β-sheet that supports a pair of parallel α-helices, forming a compact αβ sandwich. (wikipedia.org)
Increase1
This project aims to find ways to increase frataxin by improving its stability and reducing its turnover in the cell. (curefa.org)
Function1
However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). (bvsalud.org)
Leads1
Frataxin insufficiency leads to decreased activity of iron-sulfur cluster enzymes, mitochondrial iron accumulation, and resultant cell death, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum ( 9 ). (frontiersin.org)
Formation1
Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. (frontiersin.org)
Protein frataxin1
Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin. (wikipedia.org)
The reason frataxin deficiency causes these symptoms is not entirely clear. (wikipedia.org)
FA is often called a degenerative disease of neurons, including those of DRG, though frataxin deficiency also affects supporting cells. (biomedcentral.com)
Homozygous1
Mice that are homozygous for this modified gene are called KIKI (knock-in knock-in), and the compound heterozygotes formed by crossing KIKI mice with frataxin knockout mice are called KIKO (knock-in knock-out). (wikipedia.org)
Gene2
Frataxin is a protein that in humans is encoded by the FXN gene. (wikipedia.org)
The final approach involves creating transgenic mice with a GAA-expanded version of the human frataxin gene. (wikipedia.org)
Chromosome1
A subset of FRDA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome. (wikipedia.org)
Reaction1
Upon entry into mitochondria, the molecules are broken down by a proteolytic reaction to yield mature frataxin. (wikipedia.org)
Results1
The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia. (wikipedia.org)
Normal2
However, even KIKO mice still express 25-36% of the normal frataxin level, and show very mild symptoms. (wikipedia.org)
Proliferating satellite cells in FA displayed many more frataxin- and ATP5B-reactive mitochondria than normal. (biomedcentral.com)
Disease2
Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a neurodegenerative disease. (wikipedia.org)
Lower levels of frataxin result in earlier disease onset and faster progression. (wikipedia.org)
Iron2
The function of frataxin is not clear but it is involved in assembly of iron-sulfur clusters. (wikipedia.org)
The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. (wikipedia.org)