Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0848771 (neurological disability)
 928 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia (FA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. The Friedreich ataxia gene (FRDA) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease as a consequence of a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency leads to excessive free radical production, dysfunction of Fe-S center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), and progressive iron accumulation in mitochondria. Frataxin may be a mitochondrial iron-binding protein that prevents this metal from participating in Fenton chemistry to generate toxic hydroxyl radicals. We investigated whether frataxin deficiency may in addition interfere with signaling pathways. First, we showed that exposure of FA fibroblasts to iron fails to produce the normally observed increase in expression of the stress defense protein manganese superoxide dismutase. This impaired induction involves a nuclear factor-kappaB-independent pathway that does not require free radical signaling intermediates. We also examined the role of frataxin in neuronal differentiation by using stably transfected clones of P19 embryonic carcinoma cells with antisense or sense frataxin constructs. We found that during retinoic acid-induced neurogenesis frataxin deficiency enhances apoptosis and reduces the number of terminally differentiated neuronal-like cells. The addition of the antioxidant N-acetyl-cysteine only rescues cells non-committed to the neuronal lineage, indicating that frataxin deficiency impairs differentiation mechanisms and survival responses through different mechanisms. Both studies suggest that some abnormalities in frataxin-deficient cells are related to free radical independent signaling pathways.
 ...
PMID:Frataxin deficiency and mitochondrial dysfunction. 1612 Mar 11

Friedreich ataxia (FA) is an autosomal-recessive disease primarily characterized by progressive neurological disability. A significant proportion of patients also present with a hypertrophic cardiomyopathy, which may, in some cases, cause premature death. FA is caused by insufficient levels of the protein, frataxin, which is involved in mitochondrial iron metabolism. All patients carry at least one copy of an intronic GAA triplet-repeat expansion that interferes with frataxin transcription. Normal chromosomes contain up to 35 to 40 GAA triplets in an Alu sequence localized in the first intron of the frataxin gene; FA chromosomes carry from approx 70 to more than 1000 GAA triplets. The molecular diagnosis of FA is, therefore, based on the detection of this expansion, which is present in homozygosity in more than 95% of the cases. The remaining patients are heterozygous for the GAA expansion and carry a frataxin point mutation as the other pathogenic allele. The expanded GAA triplet repeat may be detected by polymerase chain reaction (PCR) amplification followed by agarose gel electrophoresis analysis. In our hands, carefully performed PCR testing, in particular, if fragment detection is enhanced by hybridization with a GAA oligonucleotide probe, is as effective in identifying patients and carriers as is Southern blot analysis of genomic DNA, and allows a more accurate sizing of the repeat. Furthermore, in the case of smaller expansions, the amplified fragment may be directly sequenced to identify very rare nonpathogenic variant repeats, such as GAAGGA. Sequence analysis of the five coding exons of the frataxin gene should be performed in clinically affected individuals who are heterozygous for an expanded GAA repeat to identify point mutations.
 ...
PMID:Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations. 1693 14

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder caused by a homozygous GAA repeat expansion mutation in intron 1 of the frataxin gene (FXN), which instigates reduced transcription. As a consequence, reduced levels of frataxin protein lead to mitochondrial iron accumulation, oxidative stress, and ultimately cell death; particularly in dorsal root ganglia (DRG) sensory neurons and the dentate nucleus of the cerebellum. In addition to neurological disability, FRDA is associated with cardiomyopathy, diabetes mellitus, and skeletal deformities. Currently there is no effective treatment for FRDA and patients die prematurely. Recent findings suggest that abnormal GAA expansion plays a role in histone modification, subjecting the FXN gene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, we investigated the efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increased FXN gene expression levels and reduced the repressive histone marks. However, no increase in frataxin protein levels was observed. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies.
 ...
PMID:HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia. 3258 97