Increased protein aggregation in Zucker Diabetic Fatty rat brain: identification of key mechanistic targets and the therapeutic application of hydrogen sulfide

BMC Cell Biology

Robert H Henning¹  Henk Buikema¹  Sjoerd W Landheer¹  Mahdi H Shishavan¹  Veroniek M Van Praag¹  Fatemeh Talaei¹ 

[1] Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, PO Box 196, 9700 AD Groningen, The Netherlands

关键词: mTOR;    Reactive oxygen species;    Fibronectin;    NaHS;    Carboxymethyllysine;    Cystathionine beta synthase;    Protein aggregates;    ZDF rats;    Autophagy;   

Others  :  855015
DOI  :  10.1186/1471-2121-15-1

 received in 2013-08-21, accepted in 2013-12-23,  发布年份 2014

【 摘 要 】

Background

Diabetes and particularly high blood glucose levels are implicated in neurodegeneration. One of the hallmarks of neurodegeneration is protein aggregation. We investigated the presence of protein aggregation in the frontal brain of Zucker diabetic fatty (ZDF) rats, an animal model for diabetes. Further, the effect of NaHS in suppressing protein aggregation in cultured brain slices from ZDF was assessed.

Results

The levels of protein synthesis, protein/gene expression, autophagy and anti-oxidant defense were evaluated in ZDF and control (Lean) brains.

Compared to Lean, ZDF brains displayed a significant increase in protein aggregates, p-tau, fibronectin expression and protein glycosylation. Increased phosphorylation of mTOR and S6 ribosomal protein in ZDF indicated higher protein synthesis, while the increase in ubiquitinated proteins and LC3-I in ZDF brains accompanied by lower LC3-II expression and LC3-II/LC3-I levels indicated the blockage of proteolytic pathways. CBS (cystathionine beta synthase) protein and mRNA expression and thiol group levels in ZDF brains were lower compared to Lean. ZDF brains show a higher level of reactive oxygen species. In vitro NaHS treatment normalized proteostasis while counteracting oxidative stress.

Conclusion

Our data demonstrate increased protein synthesis and aggregation in the diabetic ZDF rat brain, which was reversible by NaHS treatment.

This is the first report on the potential use of NaHS as a novel strategy against protein aggregation in diabetic brain.

【 授权许可】

   
2014 Talaei et al.; licensee BioMed Central Ltd.

【 图 表 】

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