Free radical stress may play a role in pathogenesis of Parkinson’s disease (PD). In this project, we study how free radicals related to reactive nitrogen (N) and oxygen (O) species cause protein misfolding, aggregation and dysfunction, and thus contribute to PD. We will test whether a specific chemical reaction of NO with proteins, co-discovered by our group and named S-nitrosylation, is increased in PD brains. Pathological formation S-nitrosylated (“SNO”) proteins may represent disease biomarkers and contribute to pathogenesis.
In this study, we will perform biochemical and chemical assays using mass spectrometry to detect S-nitrosylation and further oxidation (loss of electrons) of specific proteins. These proteins include protein-disulfide isomerase, parkin, Peroxiredoxin II, and XIAP. We will analyze brain tissues and cerebrospinal fluid obtained from the Arizona Parkinson’s Disease Consortium (APDC). Additionally, our innovative mass spectrometry techniques will identify new protein targets for S-nitrosylation affected in PD. We will assess the change of these redox (electron transfer)-mediated protein modifications in different categories of PD and PD-related diseases. Thus, this investigation will reveal novel relationships among pathological accumulation of S-nitrosylated/oxidized proteins, clinical signs of the disease, including motor and neuropsychological findings, and pathological features, such as the presence of Lewy bodies and alpha-synuclein abnormalities.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, there are no established treatments that target aberrant redox signaling in PD and related diseases. Our research allows innovative discoveries concerning oxidative and nitrosative changes that produce neuronal damage in these disease processes. We therefore believe that this study will discover novel therapeutic targets as well as specific biomarkers for PD at different pathological stages.
This study will demonstrate changes in specific proteins that undergo redox (electron transfer) reactions in PD brains. These reactions occur between proteins and reactive oxygen and nitrogen species. One such chemical reaction that we discovered with our colleagues is termed S-nitrosylation. Comprehensive information on the identity of S-nitrosylated proteins in the brains of PD patients will provide a valuable resource, allowing scientists to link chemical changes in PD with the development of new disease biomarkers and novel therapies.