scholarly journals SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

2019 ◽  
Vol 47 (20) ◽  
pp. 10728-10743 ◽  
Author(s):  
Carlotta Bon ◽  
Riccardo Luffarelli ◽  
Roberta Russo ◽  
Silvia Fortuni ◽  
Bianca Pierattini ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Monogenic Disease ◽  
Transcriptional Level ◽  
Gene Encoding ◽  
Mitochondrial Aconitase ◽  
Non Coding Rnas ◽  
Gaa Repeats

Abstract Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

scholarly journals Effect of a Valine Load Test on Plasma Alpha-Keto Acids in Friedreich Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 239-242 ◽  
Author(s):  
A. Barbeau ◽  
M. Bertrand ◽  
R. Bouchard ◽  
G.L. Gauthier ◽  
J.P. Bouchard
Keyword(s):  
General Trend ◽  
Genetic Defect ◽  
Friedreich Ataxia ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Load Test ◽  
Keto Acids ◽  
Branched Chain

SUMMARY:To test the physiological significance in vivo of our previous in vitro finding of reduced valine dehydrogenase (VDH) activity inpatients with Friedreich’s Ataxia, we subjected ataxic patients and controls to an oral valine load test (1.0g) and measured the levels of branched chain α-keto acids in the plasma for 24 hours. We demonstrated a significantly higher peak for α-keto isovaleric acid in Friedreich’s Ataxia and a general trend towards higher than control values in all other α-keto acids measured, and at all times in the experiment. These changes are compatible with the postulated defect in regulation of the activity of VDH in this illness, but because of their small amplitude, they also indicate that a VDH – deficiency is not the genetic defect in Friedreich’s A taxia.

Structural properties of Friedreich’s ataxia d(GAA) repeats

1999 ◽  
Vol 1444 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Iang-Shan Suen ◽  
Jamie N. Rhodes ◽  
Mellisa Christy ◽  
Brian McEwen ◽  
Donald M. Gray ◽  
...  
Keyword(s):  
Structural Properties ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Repeats

scholarly journals Effects of Friedreich's ataxia GAA repeats on DNA replication in mammalian cells

2012 ◽  
Vol 40 (9) ◽  
pp. 3964-3974 ◽  
Author(s):  
Gurangad S. Chandok ◽  
Mayank P. Patel ◽  
Sergei M. Mirkin ◽  
Maria M. Krasilnikova
Keyword(s):  
Dna Replication ◽  
Mammalian Cells ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Repeats

scholarly journals Amino Acid Metabolism in Friedreich's Ataxia

1976 ◽  
Vol 3 (4) ◽  
pp. 373-378 ◽  
Author(s):  
B. Lemieux ◽  
A. Barbeau ◽  
V. Beroniade ◽  
D. Shapcott ◽  
G. Breton ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Aspartic Acid ◽  
Plasma Levels ◽  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Physiological Importance ◽  
And Control ◽  
Csf Concentration

SUMMARY:A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreich's ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the resence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other β-amino acids in Friedreich's ataxia.

scholarly journals Molecular Analysis of Friedreich's Ataxia in Macedonian Patients

2008 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
S Kocheva ◽  
S Trivodalieva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Molecular Analysis ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Autosomal Recessive Inheritance ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
The Republic ◽  
Gaa Repeats ◽  
Frataxin Gene

Molecular Analysis of Friedreich's Ataxia in Macedonian PatientsFriedreich's ataxia (FRDA) is rare a progressive neurodegenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spinocerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frataxin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.

scholarly journals A Possible Genetic Pattern of Taurine Urinary Excretion in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 209-215 ◽  
Author(s):  
A. Barbeau ◽  
F. Patenaude ◽  
G. Nadon ◽  
M. Charbonneau ◽  
T. Cloutier
Keyword(s):  
Urinary Excretion ◽  
Autosomal Recessive ◽  
Genetic Defect ◽  
High Capacity ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Uptake System ◽  
Genetic Pattern ◽  
Before And After ◽  
Normal Controls

SUMMARY:The taurine urinary excretion pattern, before and after an oral load of 250 mg taurine, was studied in normal control subjects and in patients with typical Friedreich’s ataxia. It was demonstrated that in both situations the ataxic patients fell within the sub-types of “intermediate” and “high taurine excretors”, while none were “low taurine excretors”. It was also demonstrated that the excretion of taurine after a load in the obligate heterozygotes parents of the ataxic patients was intermediate between normal controls and patients. It is postulated that patients with Friedreich’s Ataxia lack normal regulation of the high affinity-low capacity uptake system for taurine (the TH system) in the brush border of kidney tubules. The low affinity-high capacity uptake system in the same membranes (the TL system) appears to be normal in Friedreich’s patients. The normal allele could be called THN and the variant THF and this trait would be inherited in an autosomal recessive fashion if it is linked to the Freidreich phenotype. Whether this finding is or is not the basic genetic defect in Friedreich’s Ataxia will require more studies to clarify, but it is of interest to note that a similar pattern appears to be present in the fibroblasts of these patients.

scholarly journals Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

Cell Reports ◽  
2016 ◽  
Vol 16 (5) ◽  
pp. 1218-1227 ◽  
Author(s):  
Jeannine Gerhardt ◽  
Angela D. Bhalla ◽  
Jill Sergesketter Butler ◽  
James W. Puckett ◽  
Peter B. Dervan ◽  
...  
Keyword(s):  
Dna Replication ◽  
Friedreich’S Ataxia ◽  
Repeat Expansion ◽  
Friedreich's Ataxia ◽  
Replication Forks ◽  
Gaa Repeats

scholarly journals Glucose Tolerance and Erythrocyte Insulin Receptors in Friedreich's Ataxia

1979 ◽  
Vol 6 (2) ◽  
pp. 233-239 ◽  
Author(s):  
P. Draper ◽  
D. Shapcott ◽  
A. Larose ◽  
J. Stankova ◽  
F. Levesque ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
Family Members ◽  
Insulin Response ◽  
Insulin Binding ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Insulin Metabolism

SummaryDetailed in vivo and in vitro studies of glucose and insulin metabolism in Friedreich's ataxia patients and unaffected family members have further defined the extent of the abnormalities in carbohydrate metabolism. The high incidence of glucose intolerance and a hyper-insulinemic response to a glucose challenge in a high percentage of Friedreich's ataxia patients has been confirmed. An increased incidence of glucose intolerance among hétérozygotes is suggested, while the siblings show a more normal distribution of diabetes and a nearly normal insulin response to the glucose tolerance test. Human growth hormone patterns are normal for all groups.Preliminary studies of insulin binding to erythrocytes suggest a difference in the binding characteristics among diabetic Friedreich's ataxia patients, while the binding in the non-diabetic Friedreich's ataxia group is similar to that of non-diabetic controls. Results from a small group of non-diabetic siblings suggest a normal insulin binding, while a tendency toward increased binding at low insulin concentrations among diabetic family members is noted.

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