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.
Highlights
Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders which result from the absence or loss of function of lysosomal proteins and characterized by the progressive accumulation of undigested material in lysosomes
We studied the pathophysiology of the L444P/L444P mutation in primary cultured fibroblasts derived from Gaucher disease (GD) patients with neurological involvement
We found mitochondrial dysfunction associated with reduced activity and expression levels of GCase in Gaucher fibroblasts
Summary
Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders which result from the absence or loss of function of lysosomal proteins and characterized by the progressive accumulation of undigested material in lysosomes. Given that cellular quality control is essential to maintaining correct mitochondrial function, it can be inferred that dysfunction of this organelle in LSDs correlates with abnormal accumulation of mitochondria, mitochondrial dysfunction and a block of autophagy[7]. SRT drugs have the potential for better CNS penetration and producing some neurological benefit as the therapeutic agent is a small molecule, such as N-butyl-1-deoxynojirimycin (NB-DNJ, Miglustat, Zavesca®), which acts as a weak inhibitor of glucosylceramide synthase, reducing the biosynthesis of GlcCer. Miglustat has been approved for use in patients with mild-to-moderate type I Gaucher disease, and is currently being evaluated in neuronopathic Gaucher patients, though a recent report showed no significant benefit for the neurological manifestations of type III patients[9]. The fact that PCs are less expensive, can be given orally and usually cross the BBB, opens up the possibility of treating Type II and Type III GD patients with neurological involvement that are not responsive to ERT
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