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

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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 (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
This work was supported by the Spanish Ministerio de Sanidad (FIS PI13/00129 grant), the Spanish Ministerio de Economía y Competitividad (contract numbers SAF2013-44021-R and CTQ2010-15848), the Junta de Andalucía (Proyectos de Investigación de Excelencia CTS-5725 and FQM-1467), the Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), the Fondo Social Europeo (FSE), by AEPMI (Asociación de Enfermos de Patología Mitocondrial) and by Mehuer Foundation.