Friedreich s ataxia

Frataxin Mitochondrial iron frataxin-mice (Cossee Friedreich s ataxia (Harding,... 

Friedreich s ataxia is caused by an intronic triplet repeat expansion. Friedreich s ataxia is an autosomal recessive disorder characterized by progressive ataxia, nystagmus, distal sensory polyneuropathy and corticospinal tract degeneration. It is caused by an unstable expanded GAA repeat in intron 1 of the frataxin gene on chromosome 9ql3. This diminishes expression of frataxin, a mitochondrial iron-storage protein that participates in free radical metabolism [71]. 

Frataxin is the protein involved in Friedreich s ataxia, the most common ataxia found in man, associated with massive iron accumulation in mitochondria. 

An inevitable consequence of ageing is an elevation of brain iron in specific brain regions, e.g. in the putamen, motor cortex, pre-frontal cortex, sensory cortex and thalamus, localized within H- and L-ferritin and neuromelanin with no apparent adverse effect. However, ill-placed excessive amounts of iron in specific brain cellular constituents, such as mitochondria or in specific regions brain, e.g. in the substantia nigra and lateral globus pallidus, will lead to neurodegenerative diseases (Friedreich s ataxia and Parkinson s disease (PD), respectively). We discuss here a few of the examples of the involvement of iron in neurodegenerative diseases. From more on iron metabolism see Crichton, 2001. 

Durr, A. (2002) Friedreich s ataxia treatment within reach, Lancet Neurol., 1, 370-374. 

It should be born in mind that normal MRC activity can be found in an organ or a tissue that does not clinically express the disease. One might deal with a tissue-specific organ deficiency, as observed in Friedreich s ataxia where iron-sulfur deficiency is barely detectable in skeletal muscle or skin fibroblasts [57]. Tissue specificity is far from being understood it is often observed even in the case of patients harboring deleterious mutation in nuclear genes with widespread expression in the organism [9]. 

Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, DeMichele G, Filla A, DeFrutos R, Palau F, Patel PI, DiDonato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich s ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 1423-1427... 

Pastore A, Tozzi G, Gaeta LM, Bertini E, Serafini V, Di Cesare S, Bonetto V, Casoni F, Carrozzo R, Federici G, Piemonte F. 2003. Actin glutathionylation increases in fibroblasts of patients with Friedreich s ataxia A potential role in the pathogenesis of the disease. J Biol Chem 278 42588 42595. 

Olivopontocerebellar Atrophy and Friedreich s Ataxia Neuropsychological Consequences of Bilateral versus Unilateral Cerebellar Lesions... 

Lodi R, Tonon C, Calabrese V, Schapira AH (2006) Friedreich s ataxia from disease mechanisms to therapeutic interventions. Antioxid Redox Signal 8 438 43 Meek D et al (1984) Ann Neurol 15 348-352... 

Fig. 1 Molecular and biochemical basis of Friedreich s ataxia (FRDA). (a) A GAA-repeat expansion in the first intron of the FRDA gene results in decreased levels of frataxin as a result of inhibition of transcriptional elongation, (b) Alterations in mitochondrial biochemistry that are associated with reduced frataxin levels. Proposed functions for frataxin include iron binding, protection and synthesis of Fe-S clusters, providing a binding partner for ferrochetalase in heme (haem) metabolism, and providing a metabolic switch between heme metabolism and Fe-S cluster biosynthesis. In FRDA, reduction of firataxin results in lowered levels of aconitase and respiratory complexes 1,11, and 111. Cytosolic proteins that contain Fe-S clusters may also be affected. Inability to form Fe-S clusters leads to an accumulation of iron, which leads to increased free radical formation (Fenton chemistry) in these organelles. Increased free radical formation may feed back to further decrease levels of Fe-S clusters, which are known to be sensitive to oxidative stress.

Cooper JM, Schapira AH (2003) Friedreich s ataxia disease mechanisms, antioxidemts and coenzyme Qio therapy. Biofactors 18 163-171... 

Diirr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (1996) Clinical and genetic abnormalities in patients with Friedreich s ataxia. N Eng J Med 335 1169-1175... 

Burnett R, et al. DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich s ataxia. Proc. Natl. Acad. Sci. U.S.A. 2006 103 11497. 

Hardirrg AE (1981) Friedreich s ataxia A clinical and gerredc study of 90 families widr an analysis of early diagrrosdc criteria and irrtrafamilial clustering of clinical features. Brairr 104 589-620. 

SCA Spinocerebellar ataxia DRPLA dentatorubal pallidolusian atrophy SBMA spinal bulbar muscular atrophy) Friedreich s disease Chamberlain S., et al.. Mapping of mutation causing Friedreich s ataxia to human chromosome 9. Nature, 1988,334, 248-250. 

Indications Alzheimer s dementia, cardiovascular disease, cerebrovascular disease, demyelination, depression, Friedreich s ataxia, improving memory, Leber s hereditary optic neuropathy Category Coenzyme Q10 analog Half-life N/A... 

Richardson TE, Kelly HN, Yu AE, Simpkins JW (2013) Therapeutic strategies in Friedreich s ataxia. Brain Res 1514 91-97... 

Over the last decade, it has become more and more widely accepted that inflammation, associated with dysfunction of metal ion homeostasis (Fe, Cu, and Zn) accompanied by concomitant oxidative stress, is a key factor in a large number of neurodegenerative diseases such as Alzheimer s disease, Parkinson s disease, Huntington s disease. Amyotrophic lateral sclerosis (ALS), multiple sclerosis, Friedreich s ataxia, and others (Crichton Ward 2006). Support comes from the observation that AD, PD, and many other neurodegenerative diseases are characterised by increased levels of some of these metal ions in specific regions of the brain. 

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