Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep10903
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Funding
- Spanish Ministerio de Sanidad [FIS PI13/00129]
- Spanish Ministerio de Economia y Competitividad [SAF2013-44021-R, CTQ2010-15848]
- Junta de Andalucia (Proyectos de Investigacion de Excelencia) [CTS-5725, FQM-1467]
- Fondo Europeo de Desarrollo Regional (FEDER-Union Europea)
- Fondo Social Europeo (FSE)
- AEPMI (Asociacion de Enfermos de Patologia Mitocondrial)
- Mehuer Foundation
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Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal beta-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are not improved by enzyme replacement therapy. Alternatively, pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the mutant enzyme represent promising alternative therapies. Here, we report on how the L444P mutation affects mitochondrial function in primary fibroblast derived from GD patients. Mitochondrial dysfunction was associated with reduced mitochondrial membrane potential, increased reactive oxygen species (ROS), mitophagy activation and impaired autophagic flux. Both abnormalities, mitochondrial dysfunction and deficient beta-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q(10) (CoQ) or a L-idonojirimycin derivative, N-[N'-(4-adamantan-1-ylcarboxamidobutyl) thiocarbamoyl]-1,6-anhydro-L-idonojirimycin (NAdBT-AIJ), and more markedly by the combination of both treatments. These data suggest that targeting both mitochondria function by CoQ and protein misfolding by PCs can be promising therapies in neurological forms of GD.
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