Frataxin‐deficient neurons and mice models of Friedreich ataxia are improved by TAT‐MTScs‐FXN treatment

Journal article

Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues. In mice models of the disease, we tested the ability of TAT-MTScs-FXN to penetrate the mitochondria and its effect on lifespan. In DRG neurons, treatment with TAT-MTScs-FXN increased cell survival, decreased neurite degeneration and reduced apoptotic markers, such as α-fodrin cleavage and caspase 9 activation. Also, we show that heat-shock protein 60 (HSP60), a molecular chaperone targeted to mitochondria, suffered an impaired processing in frataxin-deficient neurons that was relieved by TAT-MTScs-FXN addition. In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia. J Cell Mol Med 2018 Feb; 22(2):834-848

Authors: Britti, E; Delaspre, F; Feldman, A; Osborne, M; Greif, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Journal of Cellular and Molecular Medicine
• Volume: 22
• Issue: 2
• Pages: 834-848
• Publication date: 2017-10-05
• DOI: 10.1111/jcmm.13365
• EISSN: 1582-4934
• ISSN: 1582-1838
• Language: English
• Keywords: Cell biology; Neurodegeneration; Aconitase; Disease; Biology; Mitochondrion; Neuroscience; Medicine; Internal medicine; Ataxia; Biochemistry; Chemistry; Molecular biology; Frataxin