Parkinson's disease and related conditions are the most common movement disorders. Pathological studies reveal abundant protein deposits in the affected neurones, mainly formed by the protein alpha-synuclein. The research community now generally accepts that the formation of alpha-synuclein deposits is an important step in development of Parkinson's disease and related dsorders.
Despite the progress which has been made in understanding the underlying disease mechanisms of these disorders, there remains an urgent need to develop methods for use in their diagnosis. This is a serious problem not only from a clinical standpoint, but also because it affects the integrity of clinical trials and epidemiological research. The development of a simple diagnostic test to aid clinical diagnosis of Parkinson's disease would be a step forward.
In this project we are planning to design a novel chemical agent that binds specifically to alpha-synuclein aggregates in the brain. The smart compound will be labeled with an MRI-detectable contrast agent. This novel smart MRI-probe will provide a new tool for an early diagnosis of Parkinson's disease, by imaging specifically alpha-synuclein aggregates either as pre-Lewy bodies or mature Lewy bodies in the brain. We will test the smart probe on in vitro models with a variety of techniques, as well as in animal models of Parkinson's disease using an MRI machine.
Final Outcome
Dr El-Agnaf. has developed smart compounds that bind specifically to early and late alpha-synuclein aggregates formed in vitro or in cell models of Parkinson’s disease. The team has shown that these compounds cross the blood-brain barrier after being injected intravenously into normal mice or rats. Pharmacokinetics and biodistribution studies demonstrated that these compounds can reach different regions in the brain, including the cortex, hippocampus, striatum, midbrain, and brain stem, within one hour after intravenous injection.
The team also investigated the potential use of smart compounds as imaging agents for alpha-synuclein aggregates in vivo. At time points 60, 70 and 80 mins after intravenous injection, there was a clear increase of fluorescence in the alpha-synuclein transgenic mouse brain, whereas the signal for the control wild-type mouse brain was unchanged. These striking differences between the transgenic and control mice were more likely due to the binding of the compound to alpha-synuclein aggregates present in the transgenic mouse brain. The team is now developing these promising imaging agents for monitoring disease progression using noninvasive MRI and PET technology.
Researchers
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Omar El-Agnaf, PhD