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Title:
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Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment
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Author:
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Britti, Elena; Delaspre, Fabien; Feldman, Anat; Osborne, Melissa; Greif, Hagar; Tamarit Sumalla, Jordi; Ros Salvador, Joaquim
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Notes:
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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 a-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.
This work was supported by grant SAF2013-44820-R from MINECO (Spain) and by FEDER (Federacion Española de Enfermedades Raras) grant. E.B. received a fellowship from the University of Lleida. |
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Subject(s):
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-Frataxin
-Dorsal root ganglia neurons
-A-fodrin/heat-shock protein 60
-Succinate dehydrogenase |
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Rights:
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cc-by (c) Britti et al., 2018
http://creativecommons.org/licenses/by/4.0/
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Document type:
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article
publishedVersion |
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Published by:
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Wiley Open Access
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Share:
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