Abstract
Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.
Highlights
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[1, 2]
To investigate the neurological and cardiac effects linked to reduced FXN levels and to create a model for testing new therapies in vivo, we sought to generate mice that develop titratable clinical and pathological features of FRDA
The results indicate that FRDAkd mice treated with dox are effectively FXN depleted in a temporal fashion and that Fxn expression can be reversed efficiently by dox removal, making it suitable for studying pathological and clinical phenotypes associated with FRDA. 113 Frataxin knockdown mice exhibit neurological deficits The major neurologic symptom in FRDA is ataxia, which in conjunction with other neurological deficits including axonal neuropathy and dorsal root ganglion loss, contributes to the gait disorder and neurological disability[8, 9]
Summary
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[1, 2]. 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[2, 3]. Identification of the causal gene led to identification of a significant number of patients with late onset, they tend to have slower progression with less severe phenotype and are associated with smaller GAA expansions[10]. This shorter expansion enables residual Fxn expression[11], modifying the classical FDRA phenotype, consistent with other data indicating that Fxn deficiency is directly related to the FRDA phenotype[12]
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