Artículo
Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease
Autor/es | Mata, Mario de la
Cotán, David Oropesa Ávila, Manuel Garrido Maraver, Juan Cordero Morales, Mario David Ortiz Mellet, Carmen Ybot González, Patricia García Fernández, José Manuel |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2015 |
Fecha de depósito | 2017-06-07 |
Publicado en |
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Resumen | Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal β-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are ... Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal β-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 β-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q10 (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. |
Identificador del proyecto | FIS PI13/00129
info:eu-repo/grantAgreement/MINECO/CTQ2010-15848 info:eu-repo/grantAgreement/MINECO/SAF2013-44021-R FQM-1467 CTS-5725 |
Cita | Mata, M.d.l., Cotán, D., Oropesa Ávila, M., Garrido Maraver, J., Cordero Morales, M.D., Ortiz Mellet, C.,...,García Fernández, J.M. (2015). Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease. Scientific Reports, 5 (10903), 1-18. |
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