Thiol redox homeostasis in neurodegenerative disease

This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc- cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed

S-nitrosation and neuronal plasticity

Nitric oxide (NO) has long been recognized as a multifaceted participant in brain physiology. Despite the knowledge that was gathered over many years regarding the contribution of NO to neuronal plasticity, for example the ability of the brain to change in response to new stimuli, only in recent years have we begun to understand how NO acts on the molecular and cellular level to orchestrate such important phenomena as synaptic plasticity (modification of the strength of existing synapses) or the formation of new synapses (synaptogenesis) and new neurons (neurogenesis). Post-translational modification of proteins by NO derivatives or reactive nitrogen species is a non-classical mechanism for signalling by NO. S-nitrosation is a reversible post-translational modification of thiol groups (mainly on cysteines) that may result in a change of function of the modified protein. S-nitrosation of key target proteins has emerged as a main regulatory mechanism by which NO can influence several levels of brain plasticity, which are reviewed in this work. Understanding how S-nitrosation contributes to neural plasticity can help us to better understand the physiology of these processes, and to better address pathological changes in plasticity that are involved in the pathophysiology of several neurological diseases. Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visitFEDER funds via Programa Operacional Factores de Competitividade (COMPETE); COST action [BM1005]; Foundation for Science and Technology (FCT, Portugal) [PTDC/SAU-OSD/0473/2012, PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014]; Spanish-Portuguese Integrated Action grant [PRI-AIBPT-2011-1015/E-10/12]; FCT [SFRH/BD/77903/2011]; I3SNS programme (ISCIII, Spanish Government

Redox regulation of tumour suppressor protein p53 : identification of the sites of hydrogen peroxide oxidation and glutathionylation

The p53 tumour suppressor protein promotes cell cycle arrest or apoptosis in response to several forms of cellular stress and DNA damage. p53 acts as a transcription factor by binding to specific DNA sequences and regulating the expression of a myriad of target genes. p53 activity is known to be influenced by several post-translational modifications and is dependent on coordination of a zinc ion within the protein core domain. Several lines of evidence have demonstrated that oxidative modification of cysteine residues within p53 can also influence the protein's activity. However, little is known regarding the molecular details of p53 oxidation. Here we analyze oxidation pathways in the p53 core domain by Fourier transform ion cyclotron resonance mass spectrometry and top-down fragmentation. Firstly, we show that p53 core domain is sensitive to oxidation by the reactive oxygen species (ROS) hydrogen peroxide and that the zinc-coordination site is the initial target for ROS-induced oxidation. Two disulfide bonds are formed involving Cys182 and the three cysteines which coordinate to zinc (Cys176, 238 and 242). This disulfide bond formation is accompanied by loss of zinc from the binding site. Secondly, an additional cysteine, Cys277, is prone to oxidation via a ROS-independent mechanism. This residue undergoes S-glutathionylation at biologically relevant reduction potentials. We discuss our findings in the context of redox regulation of p53 activity and in comparison to other redox regulated proteins