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

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

doi:10.1186/1471-2121-15-1

Sjoerd W Landheer, Mahdi H Shishavan

Open Access

https://doi.org/10.1186/1471-2121-15-1

Copy DOI

Abstract

BackgroundDiabetes 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.ResultsThe 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.ConclusionOur 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.

Highlights

Diabetes and high blood glucose levels are implicated in neurodegeneration
As we found changes in brain proteostasis to coincide with lower levels of brain thiol groups and diminished expression of cystathionine beta synthase (CBS) in Zucker diabetic fatty (ZDF), we sought as a second aim to investigate a potential beneficial effect of H2S
The ratio of LC3-II-to-LC3-I in ZDF brains was two times lower compared to Lean brains showing lower autophagy levels in ZDF brains

Summary

Introduction

Diabetes and high blood glucose levels are implicated in neurodegeneration. We investigated the presence of protein aggregation in the frontal brain of Zucker diabetic fatty (ZDF) rats, an animal model for diabetes. As neurodegenerative diseases are often characterized by defects in brain protein maintenance [9], we employed an inbred model for type 2 diabetes the fa/fa Zucker diabetic fatty (ZDF) rat to study the effects of high glucose concentration on protein expression in brain. MTOR is an important regulator of neuronal development and function, including tau expression [16], to date only few studies have addressed a possible implication of mTOR in diabetes in relation to protein aggregate formation in brain tissue. Considering the induction of mTOR by high glucose levels [17], the mTOR pathway is likely implicated in the induction of brain protein aggregation in diabetes [18]. The presence of oxidative stress due to reactive oxygen species (ROS), and increased protein glycosylation leading to protein-protein crosslinking or aggregation [19] might be additional factors involved

Objectives

Methods

Results

Conclusion