Globotriaosylsphingosine induces oxidative DNA damage in cultured kidney cells

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Fabry disease (FD) is a lysosomal storage disorder resulting from deficient alpha-galactosidase A activity.
• Accumulation of substrates, like globotriaosylsphingosine (lyso-Gb3), causes systemic tissue damage in FD.
• Elevated DNA damage levels are observed in FD patients, suggesting a role in disease progression.

Purpose of the Study:

• To investigate the effect of lyso-Gb3 on DNA damage in cultured human embryonic kidney cells (HEK-293 T).
• To determine the nature of DNA damage induced by lyso-Gb3 in a renal cell model relevant to FD complications.

Main Methods:

• Cultured HEK-293 T cells were treated with lyso-Gb3 at concentrations found in FD patients.
• DNA damage was assessed using the alkaline comet assay.
• The origin of DNA damage (oxidative) was investigated using comet assays with specific endonucleases.

Main Results:

• Lyso-Gb3 induced significant DNA damage in HEK-293 T cells.
• The induced DNA damage was of oxidative origin, affecting both purines and pyrimidines.
• These findings link lyso-Gb3 accumulation to a specific type of cellular damage relevant to FD.

Conclusions:

• Lyso-Gb3 has a direct deleterious effect on renal cells by inducing oxidative DNA damage.
• This study provides novel insights into the molecular mechanisms underlying tissue damage in Fabry disease.
• Understanding lyso-Gb3's role in DNA damage may inform the development of new therapeutic strategies for FD.