Patients with Gaucher disease display systemic oxidative stress dependent on therapy status

Abstract

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.

Keywords: ACE, angiotensin converting enzyme; Antioxidants; CHITO, chitotriosidase; CNS, central nervous system; ERT, enzyme replacement therapy; GCase, glucocerebrosidase; GD, Gaucher disease; GD1, Type 1 Gaucher disease; GD2, Type 2 Gaucher disease; GD3, Type 3 Gaucher disease; GPG, Glycine-Proline-Glutamate; GPx, glutathione peroxidase; GSH, glutathione; GSSG, inactive, oxidized form of glutathione; Gaucher disease; Glutathione; HPLC, high performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; Lipid peroxidation; Lyso-GL1, glucosylsphingosine; MDA, malondialdehyde; NYU, New York University; Oxidative stress; RBC, red blood cell; ROS, reactive oxygen species; SOD, superoxide dismutase; SRT, substrate reduction therapy; TAC, total antioxidant capacity; TBARS, thiobarbituric acid reactive substances; TRAP, tartrate resistant acid phosphatase; UMN, University of Minnesota.

Conflict of interest statement

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.

Figures

Fig. 1

Total GSH levels and GSH/GSSG redox ratio in red blood cell lysates from treated or untreated participants with GD1 and healthy controls determined using LC-MS/MS method. Values are expressed as mean (represented by the dark closed dots) and 95% confidence intervals by group. Each small dot shows the average of values obtained at three different time points from each participant. *p < 0.05 and ** p ≤ 0.001 in comparison to healthy controls; #p < 0.01 between untreated and treated GD1.

Fig. 2

Antioxidant enzymatic activity in untreated and treated GD1 and healthy controls. Catalase (CAT; panel A), superoxide dismutase (SOD; panel B) and glutathione peroxidase (GPx; panel C) activity in red blood cell lysates were determined colorimetrically. Values are expressed as mean (represented by the dark closed dots) and 95% confidence intervals by group. Each small dot represents the average of values obtained at three different time points from each participant. *p < 0.01 and ** p ≤ 0.001 in comparison to healthy controls; $p < 0.05 and #p < 0.01 between untreated and treated GD1.

Fig. 3

Lipid peroxidation (measures as MDA-TBA adduct) and protein carbonylation in plasma from untreated and treated GD1 participants and healthy control. Values are expressed as mean (represented by the dark closed dots) and 95% confidence intervals by group. Each small dot indicates the individual mean values obtained after assessing three independent blood samples from each participant. ** p ≤ 0.001 in comparison to healthy controls; $p < 0.05 between untreated and treated GD1.