Oxidized DJ-1 as a biomarker for Parkinson's disease
The research from this grant has continued with the supplementary grant:
Mutations in the DJ-1 gene are associated with an early-onset familial form of PD and DJ-1 protein has been shown to be decreased in the CSF of sporadic PD compared to controls. DJ-1 protects nerve cells against oxidative stress. Oxidative stress has been implicated in the pathogenesis of PD. Oxidized DJ-1 may be a more sensitive biomarker for oxidative stress associated with the development and progression of PD. The goals of this study are: 1) To develop new methods for routine detection of the oxidized forms of DJ-1; and 2) To test preliminary feasibility of whether oxidized DJ-1 can be used as a biomarker for PD onset and progression.
We will take several parallel approaches. First, we will determine if a newly identified chemical modification strategy can be used to detect the mildest oxidation form of DJ-1. Secondly, we will adapt a well characterized protein carbonyl detection system for detection of the other forms of DJ-1 oxidation. Third, in conjunction with colleagues at Covance, we will develop polyclonal antibodies for the specific detection of the highest oxidation form of DJ-1.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The identification of these biomarkers for PD has the potential to monitor PD progression, which will improve patient care by providing a metric for treatment efficacy. In addition, PD biomarkers facilitate the drug discovery process and aid in the recruitment and performance of clinical trials.
Successful completion of the goals of this project will result in the development of new tools for detection of oxidized DJ-1 and the application of these tools to determine if oxidized DJ-1 is a biomarker for PD. As DJ-1 may play an important role in PD pathogenesis, new tools for detecting oxidized DJ-1 may also contribute to an improved understanding of PD.
Mutations in the DJ-1 gene are causal for an early-onset form of PD. DJ-1 protects nerve cells against oxidative stress. Oxidization of the cysteine residues in DJ-1 occurs as a consequence oxidative stress, but is also necessary to fully activate DJ-1 function.
Oxidized DJ-1, or the ratio of oxidized to total DJ-1, may be a sensitive biomarker for oxidative stressassociated with the onset and progression of PD and other neurological diseases.
Currently, the extent of DJ-1 oxidation is determined by physiochemical means which poses a practical limitation for routine analysis in blood and CSF. In these studies we developed polyclonal antibodies that detect the highest oxidized form of DJ-1. We have established that the antibodies are specific and sensitive tools for the detection of oxidized DJ-1. We have applied these tools to the detection of oxidized DJ-1 in RBC lysates from PD patients and control subjects. We have established the presence of oxidized DJ-1 in RBC lysates and determined that oxidized DJ-1 is present in sufficient abundance to warrant further biomarker assay development.
H. Houston Merritt Professor of Neurology and Chief of the Movement Disorders Division at Columbia University
Location: New York, New York, United States