It is estimated that as many as 60% to 70% of diabetic patients develop neuropathy, and the prevalence of neurodegeneration in the central nervous system (CNS) is reported to reach 40%. Diabetic patients are supposed to suffer greater risks of vascular dementia and Alzheimer disease. However, the mechanism behind is poorly understood.

Professor CHEN Chang’s group at the Institute of Biophysics (IBP) of Chinese Academy of Sciences revealed a novel mechanism which links hyperglycemia with CNS neurotoxicity. The study was published in Autophagy.

Researchers found that there is excess production of NO in the hippocampal neurons under hyperglycemic environment in diabetes. Macroautophagy/autophagy was suppressed in the hippocampus of diabetic GK rats with hyperglycemia, whereas it was unchanged in ob/ob mice without hyperglycemia.

Further study showed that core autophagy protein, ATG4B undergoes concomitant S-nitrosation, which compromises the enzyme activity of ATG4B and leads to defective phagophore expansion. Consequently, the activity of protective autophagy is decreased and leads to hippocampal neuronal cell death. They discovered that autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia.

This study sheds new light on linking hyperglycemia with CNS neurotoxicity and indicated that the inhibition of ATG4B S-nitrosation may represent a novel approach to alleviate diabetic dementia. S-nitrosation is a novel post-transcriptional modification of the core autophagy machinery.

This work was supported by Chinese Ministry of Science and Technology Project and the National Natural Science Foundation of China.

Figure: Model for the role of ATG4B S-nitrosation in hyperglycemic neurotoxicity (Image by IBP)