Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich's Ataxia Transgenic Mice.

Lucía Calatrava-Ferreras,Javier Regadera,Juan Velasco-Martín,María Casarejos,Rafael Gonzalo-Gobernado,Juan José Díaz-Gil,Manuela Vallejo-Muñoz,Antonio Herranz,Eulalia Bazán,Adriano Jiménez-Escrig,Diana Reimers

doi:10.3390/ijms17122066

Abstract

Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

Highlights

Cerebellar ataxias (CA) include a group of diseases characterized by a lack of motor coordination mainly related with dysfunction of the cerebellum and associated neuronal circuits
In the experimental model of Friedreich ataxia (FA) used in this study (YG8R mouse), liver growth factor (LGF) treatment prevented neuronal loss and reduction of Complex IV expression in association with an increase in Frataxin and in P-Akt/Akt ratio in the spinal cord; it increased Bcl2/Bax ratio in the brain stem and cerebellum; it reduced hypertrophy in the heart; and it reduced the ratio of oxidized glutathione versus reduced glutathione in skeletal muscle
Our results show that LGF upregulates Bcl2/Bax ratio in the cerebellum and brain stem of YG8R mice, indicating a potential neuroprotective effect of the factor in these brain structures that are affected in FA patients

Summary

Introduction

Cerebellar ataxias (CA) include a group of diseases characterized by a lack of motor coordination mainly related with dysfunction of the cerebellum and associated neuronal circuits. Friedreich ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of transcription of frataxin (FXN), its encoded protein, causing a multisystem disorder disease that includes neurological damage, mainly spinocerebellar ataxia, and non-neurological signs such as hypertrophic cardiomyopathy and diabetes Mellitus type 2. Because the success of these therapies for FA is limited [6], there is a need to search for new molecules with beneficial effects on damaged organs in order to ameliorate the quality of life of FA patients

Results

Discussion

Conclusion