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Title

Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease

AuthorsMata, Mario de la ; Cotán, David ; Oropesa-Ávila, Manuel; Garrido-Maraver, Juan; Cordero, Mario D. ; Villanueva Paz, Marina; Delgado Pavón, Ana; Alcocer-Gómez, Elísabet; Lavera, I. de; Ybot, Patricia; Zaderenko, Paula; Ortiz-Mellet, Carmen; García-Fernández, José Manuel; Sánchez-Alcázar, José Antonio
Issue Date2015
PublisherNature Publishing Group
CitationScientific Reports 5: 10903 (2015)
AbstractGaucher 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 (NAdBTAIJ), 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
DescriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.
Publisher version (URL)http://dx.doi.org/10.1038/srep10903
URIhttp://hdl.handle.net/10261/116973
DOI10.1038/srep10903
ISSN2045-2322
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