Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by expansion of a GAA·TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Repeat expansion results in transcriptional silencing through an epigenetic mechanism, resulting in significant decreases in frataxin protein in affected individuals. Since the FXN protein coding sequence is unchanged in FRDA, an attractive therapeutic approach for this disease would be to increase transcription of pathogenic alleles with small molecules that target the silencing mechanism. We review the evidence that histone postsynthetic modifications and heterochromatin formation are responsible for FXN gene silencing in FRDA, along with efforts to reverse silencing with drugs that target histone modifying enzymes. Chemical and pharmacological properties of histone deacetylase (HDAC) inhibitors, which reverse silencing, together with enzyme target profiles and kinetics of inhibition, are discussed. Two HDAC inhibitors have been studied in human clinical trials and the properties of these compounds are compared and contrasted. Efforts to improve on bioavailability, metabolic stability, and target activity are reviewed...Continue Reading
The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure
Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo.
GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases
The high-resolution structure of the triplex formed by the GAA/TTC triplet repeat associated with Friedreich's ataxia
The GAA*TTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner
Sticky DNA, a self-associated complex formed at long GAA*TTC repeats in intron 1 of the frataxin gene, inhibits transcription
DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich's ataxia
Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group
Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia
The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)
Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression
Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription
Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich's ataxia patients and in a mouse model
Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia
Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model
Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia
A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model
Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model
Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease
Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia
Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo
Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia
Pharmacological Reactivation of the Silenced FMR1 Gene as a Targeted Therapeutic Approach for Fragile X Syndrome
The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models
Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
Patient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies.
Mechanistic Exploration of Methionine 274 Acting as a "Switch" of the Selective Pocket Involved in HDAC8 Inhibition: An in Silico Study.
Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory
Cancer Epigenetics & Metabolism (Keystone)
Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on the relationship between cell metabolism, epigenetics and tumor differentiation.
Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.