Objective/Rationale:
Oxidative and nitrosatvie stress, related to reactive nitrogen (N) and oxygen (O) species, can cause protein misfolding, aggregation and dysfunction, and thus contribute to the development of Parkinson’s disease (PD). In this project, we will test whether a specific chemical reaction of nitric oxide (NO) with proteins, termed S-nitrosylation, which was co-discovered by our group, is altered in biological samples obtained from PD patients. Pathological formation of S-nitrosylated (“SNO”) proteins may represent disease biomarkers and contribute to pathogenesis.
Project Description:
In this study, we will perform biochemical analyses and chemical assays using mass spectrometry to detect S-nitrosylation of specific proteins in PD. We will assess the change of these redox (electron transfer)-mediated protein modifications in PD cerebrospinal fluid or serum samples obtained from PD patients during the DATATOP (Deprenyl And Tocophenol Antioxidative Therapy of Parkinsonism) trial. Additionally, our innovative mass spectrometry techniques will potentially identify new protein targets for S-nitrosylation affected in PD. Our proposed project should allow us to investigate (a) if S-nitrosylation status is specifically correlated to PD stage and possibly prevented by DATATOP treatment, and (b) if these protein modifications can serve as biomarkers for PD and PD-related disorders.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, there are no biomarkers that target aberrant redox signaling in PD and related diseases. Our research approach will allow innovative discoveries concerning oxidative and nitrosative changes that correlate to disease progression. We believe that this study will discover novel, specific biomarkers for PD, and thus greatly impact future PD diagnosis and treatment.
Anticipated Outcome:
We anticipate that this study will demonstrate S-nitrosylation of specific proteins (termed SNO-proteins) in cerebrospinal fluid or serum during progression of PD. Additionally, comprehensive analysis to find additional SNO-proteins in PD patients will provide a valuable resource, allowing scientists to link chemical changes to progression of PD and will provide potential new PD Biomarkers that should aid in diagnosis and treatment assessment.
Final Outcome
In order to find and test new effective therapies for Parkinson’s disease, the development and validation of sensitive biomarkers that can monitor the efficacy of medications are needed. In this study, we investigated if the nitric oxide-mediated post-translational modification of proteins (known as S-nitrosylation) is a useful biomarker for Parkinson’s disease (PD). Under the current funding support, we determined the levels of S-nitrosylated (or “SNO-“) proteins in biological samples, including serum and cerebrospinal fluid, that had been obtained from the DATATOP clinical trial treating patients with drug deprenyl, which among other actions is an anti-oxidant that might prevent aberrant S-nitrosylation (SNO-) reactions on proteins. Using biochemical and mass spectrometry approaches, we found that deprenyl treatment indeed decreased the serum levels of specific S-nitrosylated proteins. This finding suggests that the detection of certain S-nitrosylated proteins may serve as potential biomarkers for monitoring the efficacy of PD drugs. To further confirm our findings, we aim to continue our analysis of S-nitrosylated proteins on additional serum samples and other fluids from PD patients.
Presentations & Publications
We are in the process of publishing our findings on S-nitrosylated proteins as Biomarkers for PD in a scientific journal.
Additionally, a recent important publication on S-nitrosylated proteins from our laboratory, although not directly an outgrowth of this project from the MJ Fox Foundation, was greatly benefitted by the methods that we perfected under the MJ Fox Foundation Grant, and for this we are extremely grateful.
Ryan SD, Dolatabadi N, Chan SF, Zhang X,Akhtar MW,Parker J,Soldner F,Sunico CR, Nagar S,Talantova M,Lee B,Lopez K,Nutter A,Shan B,Molokanova E,Zhang Y,Han X,Nakamura T,Masliah E,Yates 3rd JR,Nakanishi N,Andreyev AY,Okamoto Si,Jaenisch R,Ambasudhan R, Lipton SA. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 2013:155;1351–1364.
June 2014