The Cerebellum

, 8:245

Friedreich’s Ataxia: From the (GAA)n Repeat Mediated Silencing to New Promising Molecules for Therapy

Article

Abstract

Friedreich’s ataxia (FRDA) is a neurodegenerative disease due to a pathological expansion of a GAA triplet repeat in the first intron of the FXN gene encoding for the mitochondrial protein frataxin. The expansion is responsible for most cases of FRDA through the formation of a nonusual B-DNA structure and heterochromatin conformation that determine a direct transcriptional silencing and the subsequent reduction in frataxin expression. Among other functions, frataxin is an iron chaperone central for the assembly of iron–sulfur clusters in mitochondria; its reduction is associated with iron accumulation in mitochondria, increased cellular sensitivity to oxidative stress and cell damage. There is, nowadays, no effective therapy for FRDA and current therapeutic strategies mainly act to slow down the consequences of frataxin deficiency. Therefore, drugs that are able to increase the amount of frataxin are excellent candidates for a rational approach to FRDA therapy. Recently, several drugs have been assessed for their ability to increase the amount of cellular frataxin, including human recombinant erythropoietin, histone deacetylase inhibitors, and the PPAR-γ agonists.

Keywords

Friedreich’s ataxia Frataxin FXN gene GAA triplet repeat Neurodegeneration 

Abbreviations

FRDA

Friedreich’s ataxia

FXN

Human frataxin gene

HDAC

Histone deacetylase

HAT

Histone acetylase

HDACi

Histone deacetylase inhibitors

rhu-EPO

Recombinant human erythropoietin

PPAR-γ

Peroxisome proliferators-activated receptor gamma

PGC1α

Human peroxisome proliferators-activated receptor gamma coactivator alpha

PEV

Position variegation effect

SIRT

Sitruin protein

IscU

Iron–sulfur cluster scaffold protein

MitoQ

Mitoquinone

DFP

Deferiprone

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Laboratoire de Neurologie Expérimentale, Hôpital ErasmeUniversité Libre de Bruxelles (ULB)BrusselsBelgium
  2. 2.Molecular Genetic Unit, Department of Molecular and Cellular Biology and Pathology, Medical Genetic SchoolUniversity “Federico II” of NaplesNaplesItaly

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