This grant builds upon the research from a prior grant: Determination of the 3D Structure of Biologically Active Small Molecules in Complex with DJ-1
Study Rationale:
Currently, there are no tools to predict whether someone is at risk of developing Parkinson’s disease or to diagnose the early stages of the disease before motor symptoms can be detected. This pre-clinical phase is targeted by many efforts to develop therapeutics to prevent or treat Parkinson’s.
Developing such tools is critical to support new drugs and will be invaluable in the future, to identify patients who will benefit from them. The investigators plan to develop a lab test, based on measuring DJ-1, a protein linked to the early onset of cases of Parkinson’s in people with a family history of the disease, known as familial Parkinson’s.
Hypothesis:
DJ-1 is a protein that exists in “switched-on” forms to protect neurons but may be “switched-off” by some of the same conditions that can cause Parkinson’s; measuring how much “off” and “ on” DJ-1 is present in someone’s body could be used as a tool to help the diagnosis of Parkinson’s in the early stages.
Study Design:
The team will develop a routine laboratory test to measure the amount of “on-DJ-1” and “off-DJ-1” in human biofluid samples. For this, they will first develop chemicals to detect each state of DJ-1. They have already developed unique chemicals that can detect one of the “on” forms of DJ-1 that should be abundant in healthy brains (reduced-DJ-1). They now need to make reagents (antibodies) against other “on” forms (oxidized-DJ-1) and against the “off” form (superoxidized-DJ-1). These chemicals will be “tagged” with colored molecules to allow us to measure what proportion of DJ-1 is on and off in samples and thus provide a snapshot of the state of health of brains cells.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
DJ-1 malfunction is believed to happen years before motor symptoms can be detected and represents a promising candidate for early detection and treatment. The chemicals we want to develop are novel and will be available for the Parkinson’s community to support multi-disciplinary efforts to find avenues for early diagnosis and therapies to protect nerve cells against damage or degeneration.
Next Steps for Development:
The aim of these initial efforts is to develop chemicals and antibodies to detect DJ-1 and provide proof that tests are able to measure the proportion of different states of DJ-1 in samples derived from human cell models. Once this “proof-of-concept” is established the team plans to validate its method using Parkinson’s patient biofluid samples. This will be the first step toward developing a test to be used by doctors to explore diagnosis.