title: Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease.
abstract: 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.
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Mario
authors.initials: M
authors.lastname: de la Mata
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: David
authors.initials: D
authors.lastname: Cotán
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Manuel
authors.initials: M
authors.lastname: Oropesa-Ávila
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Juan
authors.initials: J
authors.lastname: Garrido-Maraver
authors.affiliation: Facultad de Odontología, Universidad de Sevilla, Sevilla.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Cordero
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Marina
authors.initials: M
authors.lastname: Villanueva Paz
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Ana
authors.initials: A
authors.lastname: Delgado Pavón
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Elizabet
authors.initials: E
authors.lastname: Alcocer-Gómez
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: Isabel
authors.initials: I
authors.lastname: de Lavera
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS)-CSIC, Hospital Virgen del Rocío, Sevilla 41013.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ybot-González
authors.affiliation: Sistemas Físicos, Químicos y Naturales-Universidad Pablo de Olavide.
authors.forename: Ana
authors.initials: A
authors.lastname: Paula Zaderenko
authors.affiliation: Dept. Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.affiliation: Instituto de Investigaciones Químicas (IIQ) CSIC-Universidad de Sevilla, Sevilla, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla.
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Alcázar
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009154:Mutation; D010588:Phagosomes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D005962:Glucosylceramidase; C024989:coenzyme Q10