Abstract
Friedreich's ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous systems, is mostly associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich's ataxia in the late 1990s, the consequence of frataxin loss of function has generated vigorous debate. Very early on we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulphur cluster synthesis and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency appears to be consistently associated with increased sensitivity to reactive oxygen species as opposed to increased oxygen radical production. By compiling the findings of fundamental research and clinical observations we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich's ataxia.
Highlights
Friedreich’s ataxia (FA), the most prevalent form of autosomal recessive cerebellar ataxia in Caucasians, is characterised by progressive ataxia and dysarthria [1]
In the vast majority of cases, it is caused by a GAA trinucleotide repeat expansion in the first intron of the frataxin-encoding gene (FXN), which results in decreased gene expression and partial loss of function of the frataxin protein in the mitochondrial matrix [2]
On the basis of recent studies of various conditions in many different organisms, including human diseases originating from mutations in genes functionally related to FXN, we tried to reconcile the various pathogenic manifestations resulting from frataxin depletion and argue for a prominent and early role of impaired responses to oxidative insults in FA
Summary
Friedreich’s ataxia (FA), the most prevalent form of autosomal recessive cerebellar ataxia in Caucasians, is characterised by progressive ataxia and dysarthria [1]. The symptoms usually become apparent around puberty, onset may occur much later in life (> 60 years old). The neurological features include sensory neuropathy, deep sensory impairment, signs of pyramidal tract involvement and progressive cerebellar dysfunction. Diabetes mellitus occurs in approximately one-third of FA patients [1]. On the basis of recent studies of various conditions in many different organisms (from microorganisms to humans), including human diseases originating from mutations in genes functionally related to FXN, we tried to reconcile the various pathogenic manifestations resulting from frataxin depletion and argue for a prominent and early role of impaired responses to oxidative insults in FA. The vicious circle hypothesis The cellular consequences of frataxin loss of function were initially described as faulty iron handling, impaired ISC synthesis and increased reactive oxygen species production [4]. We and others hypothesized that a vicious circle might link these three abnormalities (Figure 2A) and that targeting any of the three would
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