Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in GBA1, which encodes for the lysosomal hydrolase enzyme, β-glucocerebrosidase. The resulting misfolded protein can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The enzyme deficiency leads to accumulation of its substrates, glucosylceramide and glucosylsphingosine, within macrophage lysosomes and with prominent disease manifestations in macrophage rich tissues. Resultant lysosomal pathology and impaired autophagy leads to redox imbalance, mitochondrial dysfunction and intracellular oxidative stress. Here we have systematically examined a role for oxidative stress in individuals affected by Gaucher disease. We compared multiple oxidative stress biomarkers in plasma and red blood cell samples from patients who are currently untreated, with those who are stable on standard-of-care therapy, and with healthy controls. We found significant differences in key oxidative stress biomarkers in untreated patients compared to healthy control. In treated patients, results generally fell between the controls and the untreated patients. Interestingly, even asymptomatic and minimally symptomatic untreated patients had evidence of significant systemic oxidative stress. We conclude that underlying oxidative stress may contribute to Gaucher disease pathophysiology including long-term adverse outcomes such as Parkinsonism and malignancies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for Gaucher disease and other lysosomal storage disorders.
|Original language||English (US)|
|Journal||Molecular Genetics and Metabolism Reports|
|State||Published - Dec 2020|
Bibliographical noteFunding Information:
Financial support was provided by Sanofi-Genzyme, Pfizer Inc. and the Lysosomal Disease Network . The Lysosomal Disease Network ( U54NS065768 ) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. Research reported in this publication was also supported by the NCATS Award Number UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
RVK and JCC has received grants from NIH, Sanofi-Genzyme, Pfizer Inc. ; NJW has received grants from Sanofi-Genzyme and Takeda-Shire , personal fees from Sanofi-Genzyme, Takeda-Shire and Pfizer Inc. , and non-financial support from Sanofi-Genzyme; MRT, RB, AT, KR and JRJ declare no conflict of interest.
© 2020 The Authors
- Gaucher disease
- Lipid peroxidation
- Oxidative stress