A guanine-adenine-adenine (GAA) trinucleotide repeat expansion within the first intron of the frataxin (Fxn) gene in the chromosome 9 is the major cause of Friedreich's ataxia (FRDA), the most commonly inherited ataxia (Chamberlain et al., 1988; Campuzano et al., 1996). Due to recessive inheritance of this GAA repeat expansion, patients have a marked deficiency of Fxn mRNA and protein levels caused by reduced Fxn gene transcription (Campuzano et al., 1996; Campuzano et al., 1997). Indeed, the GAA expansion size has been shown to correlate with residual Fxn levels, earlier onset, and increased severity of disease (Filla et al., 1996; Montermini et al., 1997). The prevalence of heterozygous carriers of the GAA expansion is between 1:60 and 1:110 in European populations, and the heterozygous carriers of a Fxn mutation are not clinically affected (Andermann et al., 1976; Harding, 1981).

FRDA is an early-onset neurodegenerative disease that progressively impairs motor function, leading to ataxic gait, cardiac abnormalities, and other medical co-morbidities, ultimately resulting in early mortality (median age of death, 35 years) (Koeppen and Mazurkiewicz, 2013; Koeppen, 2011). However, identification of the causal gene led to identification of a significant number of patients with late onset, tend to have slower progression with less severe phenotype and are associated with smaller GAA expansions (Bhidayasiri et al., 2005). This shorter expansion enables residual Fxn expression (Li et al., 2015), thus modifying the classical FRDA phenotype, consistent with other data indicating that Fxn deficiency is directly related to the FRDA phenotype (Seibler et al., 2005). Extra-neurologic symptoms including metabolic dysfunction and insulin intolerance are observed in the majority and frank type I diabetes is observed in approximately 15% of patients, the severity of which is related to increasing repeat length (Martinez et al., 2017; Galea et al., 2016; Coppola et al., 2009). The mechanisms by which Fxn reduction leads to clinical symptoms and signs remain to be elucidated, but molecular and cellular dysfunction mediated by a critical reduction in Fxn levels plays a central role (Pandolfo, 2002).

FXN is a nuclear-encoded mitochondrial protein involved in the biogenesis of iron-sulphur clusters, which are important for the function of the mitochondrial respiratory chain activity (Abrahão et al., 2015; Tanaka et al., 1996). Studies in mouse have shown that Fxn plays an important role during embryonic development, as homozygous frataxin knockout mice display embryonic lethality (Cossée et al., 2000), consistent with FXN’s evolutionary conservation from yeast to human (Campuzano et al., 1996; Campuzano et al., 1997). Over the past several years, multiple mouse models of frataxin deficiency, including a knock-in knockout model (Miranda et al., 2002), repeat expansion knock-in model (Miranda et al., 2002), transgenic mice containing the entire Fxn gene within a human yeast artificial chromosome, YG8R and YG22R (Al-Mahdawi et al., 2004; Al-Mahdawi et al., 2006), as well as a conditional Fxn knockout mouse, including the cardiac-specific (Puccio et al., 2001) and a neuron specific model (Puccio et al., 2001) have been generated. These existing transgenic and heterozygous knockout FRDA animal models are either mildly symptomatic or restricted in their ability to recapitulate the spatial and temporal aspects of systemic FRDA pathology when they are engineered as tissue-specific conditional knockouts (Miranda et al., 2002; Al-Mahdawi et al., 2004; Al-Mahdawi et al., 2006; Puccio et al., 2001; Simon et al., 2004; Perdomini et al., 2013). Despite advances made towards elucidating FRDA pathogenesis, many questions remain due to the need for mouse models better recapitulating key disease features to understand frataxin protein function, disease pathogenesis, and to test therapeutic agents.

In this regard, one crucial question facing therapeutic development and clinical trials in FRDA is the reversibility of symptoms. The natural history of the disorder has been well described (Metz et al., 2013; Nakashima et al., 2014), it is not known how clinical features such as significant motor disability relate to reversible processes (e.g. underlying neuronal dysfunction) or reflect irreversible cell death. It is often assumed that clinically significant ataxia and motor dysfunction reflects neurodegeneration, although this may not be the case. This issue, while critically important for therapeutic development, is difficult to address in patients, but we reasoned that we could begin to address this question in an appropriate mouse model.

Here we report an inducible mouse model for FRDA, the FRDAkd mouse, that permits reversible, and yet substantial frataxin knockdown, allowing detailed studies of the temporal progression, or recovery following restoration of frataxin expression - the latter permitting exploration of disease reversal given optimal treatment (normalization of Fxn levels). We observe that Fxn knockdown leads to behavioral, physiological, pathological, and molecular deficits in FRDAkd mice paralleling those observed in patients, including severe ataxia, cardiac conduction defects and increased left ventricular wall thickness, iron deposition, mitochondrial abnormalities, low aconitase activity, and degeneration of dorsal root ganglia and retina, as well as early mortality. We identify a signature of molecular pathway dysfunction via genome-wide transcriptome analyses, and show reversal of this molecular phenotype and as well as behavioral and pathological measures, even in the setting of significant disability due to motor dysfunction in FRDAkd animals.

Here we report development and extensive characterization of a novel, reversible mouse model of FRDA based on knock-down of frataxin by RNA interference (Seibler et al., 2007), the FRDAkd mouse. Treated transgenic mice developed abnormal mitochondria, exhibit cardiac and nervous system impairments along with physiological, pathological and molecular deficits. These abnormalities likely contributed to the behavioral phenotype of FRDAkd mice, parallel to what is observed in FRDA patients (Koeppen and Mazurkiewicz, 2013; Koeppen, 2011). Importantly, restoration of Fxn expression, even after the development of severe symptoms and pathological defects, resulted in a drastic amelioration of the clinical phenotype, both in the cardiac and nervous systems, including motor activity. Pathology was significantly improved in the heart, DRGs and in the retina, but only mild improvement was observed in spinal cord, suggesting Fxn restoration for the duration of 8 weeks is not sufficient for reversal of neuronal defects in the spinal cord after Fxn knockdown. Interestingly, transcriptomic changes due to Fxn knockdown in three different tissues differed (Coppola et al., 2009), indicating variable response to frataxin deficiency, which could partly explain cell and tissue selectivity in FRDA (Lynch et al., 2012). The onset and progression of the disease correlates with the concentration of doxycycline (shRNA induction), and the phenotype returns to baseline after its withdrawal. Since off-target effects due to the shRNA induction are of concern in any RNAi based experiments, we examined the off-target effect by determining the shRNA specificity and measuring changes in gene expression pattern during the induction of shRNA expression targeting the Fxn gene. Fxn was the earliest and most consistent gene showing significant down-regulation and we did not observe any changes in the RNA levels of other potential targets at any stage in our analyses, indicative of the absence of significant off-target effects. The onset of transgene expression to achieve Fxn knockdown and robust recovery of symptoms due to restoration of Fxn levels in a mouse model of FRDA, even when reversed after the onset of the disease, makes this model an appealing potential preclinical tool for developing FRDA therapeutics. This approach will also enable new insights into FRDA gene function and molecular disease mechanisms.

Several models of FRDA have been developed and each have advantages and disadvantages (Perdomini et al., 2013). This new FRDAkd model exhibits several unique features that provide advantages for the study of FRDA pathophysiology relative to other existing models (Miranda et al., 2002; Al-Mahdawi et al., 2004; Al-Mahdawi et al., 2006; Puccio et al., 2001; Simon et al., 2004; Perdomini et al., 2013). First, induction of frataxin knockdown permits circumventing potential confounding developmental effects (Cossée et al., 2000) and has the flexibility to enhance the disease onset and progression very rapidly by increasing the doxycycline dose. Moreover, the temporal control of Fxn knockdown can provide further insights into the sequence of tissue vulnerability during the disease progression (Lynch et al., 2012). Second, reversibility of Fxn knockdown provides a unique model to mimic the effect of an ideal therapeutic intervention. Along this line, it has so far not been established to what extent FXN restoration after the onset of clinical motor symptoms is successful to prevent occurrence and/or progression of FRDA. Therefore, this model will be of central importance to gain better insights into disease pathogenesis and to test therapeutic agents. Third, the doxycycline-dependent reduction of Fxn expression can be tailored to carefully determine the critical threshold of Fxn levels necessary to induce selective cellular dysfunction in the nervous system (DRGs and spinal cord) and to understand the occurrence of tissue specific dysfunction in FRDA. Thereby, these experiments will help to understand the tissue specificity and generate clinically relevant tissue targeted therapeutics for FRDA. Finally, the temporal control of single copy and reversible regulation of shRNA expression against Fxn produces reproducible transgene expression from the well-characterized rosa26 locus to generate the first model to exhibit and reverse several symptoms parallel to FRDA patients. Here, we focused on the consequences of frataxin removal in an otherwise healthy adult animal. However, we should emphasize that this FRDAkd model uniquely facilitates future studies exploring prenatal or early post natal knockdown, and a wide variety of time course studies to understand disease pathophysiology and to identify potential imaging, physiological, or behavioral correlates of likely reversible or non-reversible disabilities in patients.

We show that FRDAkd animals are defective in several behaviors and exhibit weight loss, reduced locomotor activity, reduced strength, ataxia and early mortality. All of these defects were significantly improved following Fxn restoration, approaching or reaching wild-type levels. Most importantly ataxia and survival are well-established and important clinical endpoints in FRDA (Tsou et al., 2011), readouts after Fxn restoration clearly improve these parameters and appear to be directly related to the functional status of the FRDAkd mice. We conclude that Fxn deficient mice exhibit considerable neurological plasticity even in a nervous system that is fully adult. Hence, utilizing these reversible intermediate behavioral phenotypes as biomarkers will help us determine the disease progression and test various FRDA treatment options in this model.

Hypertrophic cardiomyopathy is a common clinical feature in FRDA and approximately 60% of patients with typical childhood onset FRDA die from cardiac failure (Tsou et al., 2011). It is generally believed that cardiac failure is caused by the loss of cardiomyocytes through activation of apoptosis (Fujita and Ishikawa, 2011). We observed activation of early apoptosis pathways in heart tissue and severe cardiomyopathy characterized by ventricular wall thickness (Bennett, 2002). However, we did not observe TUNEL positive cells in either heart or nervous system. This may reflect that the model is in a early phase of cell death initiation, or rather that apoptotic cells are readily phagocytosed by neighboring cells and are consequently difficult to detect (Ravichandran, 2011). We also observed enhanced activation of autophagy in the heart tissue of FRDAkd mice, where autophagic cardiomyocytes are observed at a significantly higher frequency during cardiac failure (Martinet et al., 2007). These results suggest that apoptosis and autophagy together might synergistically play a vital role in the development of cardiac defect in FRDA (Eisenberg-Lerner et al., 2009).

During Fxn knockdown, FRDAkd mice initially exhibited a long QT interval at 12 weeks during electrocardiographic analyses, followed by the absence of P-waves and increased ventricular wall thickness at 24 weeks. Restoration of Fxn levels at 12 weeks reversed long QT interval phenotype. However, it will be interesting to examine if the ventricular wall thickness can be restored by a more prolonged rescue time period. Another prominent feature of Fxn deficiency mouse and FRDA patients is iron accumulation and deficiency in activity of the iron-sulfur cluster dependent enzyme, aconitase, in cardiac muscle (Puccio et al., 2001; Rötig et al., 1997; Delatycki et al., 1999; Michael et al., 2006). Consistent with these observations, we observed increased iron accumulation and reduced aconitase activity in the cardiac tissue of FRDAkd mice and we demonstrate a marked reversal of both to a statistically significant extent, suggesting Fxn restoration is sufficient to overcome and clear the iron accumulation and reverse aconitase activity (Tan et al., 2001). Our gene expression data revealed several genes (Hfe [Del-Castillo-Rueda et al., 2012], Slc40a1 [Del-Castillo-Rueda et al., 2012], Hmox1 [Song et al., 2012], Tfrc [Del-Castillo-Rueda et al., 2012] and Gdf15 [Cui et al., 2014]) directly involved in hemochromatosis and iron overload to be upregulated in our FRDAkd mice, all of which were rescued to normal levels by frataxin restoration. Similarly, several downregulated genes involved in normal cardiac function (Cacna2D1, Abcc9 and Hrc) were rescued by Fxn restoration. Together, these data indicate that Fxn restoration in symptomatic FRDAkd mice reverses the early development of cardiomyopathy at the molecular, cellular and physiological levels.

Cellular dysfunction due to FXN deficiency is presumed to be the result of a mitochondrial defect, since FXN localizes to mitochondria (Tan et al., 2001; Koutnikova et al., 1997; Foury and Cazzalini, 1997) and deficiencies of mitochondrial enzymes and function have been observed in tissues of FRDA patients (Rötig et al., 1997; Lodi et al., 1999). It has been hypothesized that FXN deficiency induced mitochondrial dysfunction involves the production of ROS, which subsequently lead to cellular dysfunction (Tamarit et al., 2016; Santos et al., 2010). Several studies have suggested the existence of ROS markers in FRDA patient samples (Schulz et al., 2000; Tozzi et al., 2002; Piemonte et al., 2001; Emond et al., 2000). However, other evidence from several different FRDA model organisms suggests that ROS are not elevated (Chen et al., 2016a; Chen et al., 2016b; Seznec et al., 2005; Shidara and Hollenbeck, 2010) and more than ten clinical trials based on antioxidant therapy have shown no or limited benefit in FRDA patients (Kearney et al., 2012). In our FRDAkd mouse model, we did not observe evidence of a chronic, sustained increase in ROS as measured by three different assays, which is consistent with recent data suggesting that FXN deficiency likely acts via other pathways (Chen et al., 2016a; Chen et al., 2016b). Here we show that FRDAkd mice displayed accumulation of damaged mitochondria, and reduced aconitase as a direct consequence of frataxin deficiency in heart, consistent with previous findings in conditional FRDA mouse models (Puccio et al., 2001; Simon et al., 2004). This is consistent with the model whereby frataxin deficiency inhibits mitochondrial function leading to cellular dysfunction (González-Cabo and Palau, 2013). Restoration of FXN resulted in improvement in pathological mitochondrial structure indicating that FXN restoration prevents mitochondrial defects and may thereby enhance cell survival (Tan et al., 2001). Our observation of mitochondrial dysfunction recovery as early as eight weeks after FXN restoration is consistent with the highly dynamic nature of mitochondrial function (Chan, 2012).

In the nervous system, we observed higher level of condensed mitochondria in DRGs through ultrastructural analyses. Condensed mitochondria are known to have lower respiratory control and ATP production (Desagher and Martinou, 2000). On most occasions, these condensed mitochondria in DRG neurons of FRDAkd mice were associated with electron-light, or ‘empty’ vesicles. Degenerating mitochondria in the nervous system can lose their cristae to become empty vesicles co-occurring with either lipid, pigment, and glycogen accumulation, may be the case here (Golestaneh et al., 2017). Nile Red staining in the FRDAkd mice was performed to examine if these empty vesicles are lipid bodies. However, while we observed lipid accumulation in these vesicles in the liver, we did not observe detectable levels of lipid staining in the DRGs, heart and spinal cord samples in either control or transgenic animals. Consistent with a mitochondrial origin for these vesicles, we did observe a reduction in condensed mitochondria and their association with these empty vesicles in rescue animals, suggesting that a substantial fraction of dysfunctioning frataxin-deficient mitochondria containing neurons are still viable after the onset of disease and that their dysfunction can be reversed. Additional experiments will be needed to identify the origin and composition of these empty vesicles in this model.

In the spinal cord, we observed reduction of axonal size and myelin sheath thickness in FRDAkd animals, however after eight weeks of rescue period by FXN restoration, we observed limited improvement, suggesting more time may be necessary for improved nervous system recovery. Conversely, disruption of photoreceptor neurons and degenerating RPE cells in the retina displayed robust recovery, indicating an overall morphological improvement in retinal neurons upon FXN restoration to normal levels. These findings extend previous studies showing that many defects in FRDA cells in vitro and cardiac function in vivo may be reversible following reintroduction of FXN (Vyas et al., 2012) by pharmacological interventions targeting aberrant signaling processes (Rufini et al., 2015) or by reintroduction of FXN by gene therapy (Perdomini et al., 2014).

Improved understanding of the mechanism by which FXN deficiency leads to the various phenotypes observed in FRDA is a major goal of current research in this disorder. In this regard, gene expression analyses identified several pathways altered, including the PPAR signaling pathway, the insulin signaling pathway, fatty acid metabolism, cell cycle, protein modification, lipid metabolism, and carbohydrate biosynthesis, all of which have been previously associated with altered function in FRDA patients (Coppola et al., 2009; Haugen et al., 2010; Coppola et al., 2006). Although we did observe iron deposition associated with Fxn knockdown, we did not observe, strong evidence of Pdk1/Mef2 activation, as previously observed in the fly and a constitutive mouse model (Chen et al., 2016a; Chen et al., 2016b). This observation may be due to differences in the timing of knockdown. The role of this specific pathway in mediating neurodegeneration needs further exploration following embryonic or early postnatal knockdown in our model and in others. We also observed several immune components, namely, complement and chemokine cascade genes being upregulated, may be implicated as a protective mechanism after Fxn knockdown, or in a causal role through chronic activation of the inflammatory response (Shen et al., 2016; Lu et al., 2009). It will be interesting to assess the causal roles of these genes and pathways and as potent candidate biomarkers for FRDA at several stages during the disease progression.

Determining definitively whether the global expression changes observed in this study are primary or secondary to Fxn knockdown will require further investigation by examining more dense time points immediately after Fxn knockdown and rescue, but our data clearly support the utility of induced models of disease, whereby the consequences of gene depletion can be more cleanly controlled to examine the molecular changes (Seibler et al., 2007). Together with post-induction rescue, this study highlights potential biomarkers and pathways of FRDA progression. For FRDA clinical trials, it will be important to assess whether these expression changes are translatable to the human disease and extend to other tissues that are more easily accessible than CNS or cardiac tissue. Together, these observations suggest that this work also provides a functional genomics foundation for understanding FRDA disease mechanism, progression and recovery.

In conclusion, we characterize a new, inducible model of Fxn deficiency and provide multiple lines of evidence that Fxn knockdown in adult mice leads to clinical – pathological features parallel to those observed in FRDA patients. By restoring FXN levels we show reversal of several symptoms even after significant motor and cardiac abnormalities, demonstrating that substantial clinical symptoms may result from reversible cellular dysfunction, rather than cell death. These data also highlight the utility of this model for testing potential therapeutics, such as gene therapy (Perdomini et al., 2014), protein replacement therapy (Vyas et al., 2012), enhancement of mitochondrial function (Strawser et al., 2014) and small molecules (Sandi et al., 2014; Kearney et al., 2016). In fact, our findings suggest that such approaches may not only enhance FXN expression and rescue downstream molecular changes, but may too alleviate pathological and behavioral deficits associated with FRDA, depending on the stage of the disorder.

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Author details

1. Vijayendran Chandran

   Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Present address

   Department of Pediatrics, School of Medicine, University of Florida, Gainesville, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Daniel H Geschwind

   For correspondence

   vijayendran@ufl.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2469-6263

2. Kun Gao

   Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

3. Vivek Swarup

   Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Project administration

   Competing interests

   No competing interests declared

4. Revital Versano

   Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Project administration

   Competing interests

   No competing interests declared

5. Hongmei Dong

   Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

6. Maria C Jordan

   Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

7. Daniel H Geschwind

   1. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
   2. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Vijayendran Chandran

   For correspondence

   dhg@mednet.ucla.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2896-3450

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