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

https://doi.org/10.1016/j.ymgmr.2020.100667Get rights and content
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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

Gaucher disease
Oxidative stress
Glutathione
Lipid peroxidation
Antioxidants

Abbreviations

ACE
angiotensin converting enzyme
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
HPLC
high performance liquid chromatography
LC-MS/MS
liquid chromatography-tandem mass spectrometry
Lyso-GL1
glucosylsphingosine
MDA
malondialdehyde
NYU
New York University
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

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