Drosophila melanogaster Models of Friedreich’s Ataxia

Received Dec 2, 2017; Revised Jan 29, 2018; Accepted Feb 28, 2018

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1. Introduction

Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder and the most common form of hereditary ataxia among populations of European origin (2–4/100,000) [1]. This disabling condition typically manifests before age 25, with progressive neurodegeneration of the dorsal root ganglia, sensory peripheral nerves, corticospinal tracts, and dentate nuclei of the cerebellum. A large proportion of patients develop hypertrophic cardiomyopathy, which is the major cause of reduced life expectancy in this disease. Diabetes mellitus and impaired glucose tolerance are also seen in a significant number of FRDA patients (reviewed in [2]).

FRDA is caused by loss-of-function mutations in the FXN gene, which encodes the frataxin protein [3]. Frataxin is a small protein encoded in the nucleus, expressed as a precursor polypeptide in the cytoplasm and imported into mitochondria [4–6]. The majority of FRDA patients are homozygous for an abnormally expanded GAA repeat in intron 1 of FXN, resulting in strongly reduced frataxin protein expression (from 5% to 30% of the normal level) [7]. The remaining FRDA patients are compound heterozygotes, carrying the GAA repeat expansion on one FXN allele and another pathogenic mutation on the other allele, including point mutations and insertion and/or deletion mutations [8].

A lack of available patients and the inherent limitations of cellular models often hinder the discovery and detailed analyses of genes and pathways relevant to the pathology of rare human disorders such as FRDA. Fortunately, the high evolutionary conservation of frataxin (Figure 1) has enabled the development of disease models in several organisms, from bacteria to mice, that have significantly contributed to the understanding of frataxin function. The development of these disease models is an essential step in elucidating underlying pathological mechanisms and identifying efficient treatments in FRDA.

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Seminal findings reported by key studies in model organisms (reviewed in [14–23]) have suggested potential roles for frataxin in iron homeostasis and cellular defense against reactive oxygen species (ROS), as an activator of the mitochondrial respiratory chain, as a mitochondrial chaperone, and...