Open Access Research article

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

Fatemeh Talaei*, Veroniek M Van Praag, Mahdi H Shishavan, Sjoerd W Landheer, Henk Buikema and Robert H Henning

  • * Corresponding author: Fatemeh Talaei Talaei@irimc.org

  • † Equal contributors

Author Affiliations

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

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BMC Cell Biology 2014, 15:1  doi:10.1186/1471-2121-15-1

Published: 6 January 2014

Abstract

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.

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