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Cited by 126Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusMetabolism and Genetic Disorders

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

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de la Mata, Mario, Cotán, David, Oropesa-Ávila, Manuel, Garrido-Maraver, Juan, Cordero, Mario D., Villanueva Paz, Marina, Delgado Pavón, Ana, Alcocer-Gómez, Elizabet +6 more·2015·Scientific Reports
DOI 10.1038/srep10903PMC PMC4456666
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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 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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Authors
de la Mata, M., Cotán, D., Oropesa-Ávila, M., Garrido-Maraver, J., Cordero, M. D., Villanueva Paz, M., Delgado Pavón, A., Alcocer-Gómez, E., de Lavera, I., Ybot-González, P., Paula Zaderenko, A., Ortiz Mellet, C., Fernández, J. M. G., & Sánchez-Alcázar, J. A.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Universidad de Sevilla (ES)
Corresponding author
Sánchez-Alcázar, José A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2015-06-05
Volume
5
Issue
1
Pages
10903-10903
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep10903
PMC
PMC4456666
OpenAlex
W1529235958
Cited by
126
References
2
Citations by year
2026: 2 · 2025: 11 · 2024: 5 · 2023: 11 · 2022: 13 · 2021: 13 · 2020: 14 · 2019: 10 · 2018: 15 · 2017: 13 · 2016: 12 · 2015: 7
FWCI
10.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Deposito de Investigacion Universidad de Sevilla (University of Seville) (publishedVersion, cc-by-nc-nd)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
Funders
  • Ministerio de Economía y Competitividad (CTQ2010-15848, SAF2013-44021R)
  • Junta de Andalucía (FQM-1467, CTS-5725)
  • Asociación de Enfermos de Patologías Mitocondriales
  • European Regional Development Fund (SAF2013-44021-R, CTS-5725)
  • European Social Fund
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Gaucher disease, beta-glucocerebrosidase, pharmacological chaperones, coenzyme Q10, mitochondrial dysfunction, mitophagy, autophagy, reactive oxygen species, mitochondrial membrane potential, lysosomal storage disease, neuronopathic Gaucher disease
MeSH terms
Autophagy, Enzyme Activation, Enzyme Inhibitors, Fibroblasts, Gaucher Disease, Glucosylceramidase, Humans, Mitochondria, Mutation, Phagosomes, Ubiquinone, Biomarkers, Gene Expression, Reactive Oxygen Species

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