A team of researchers from National University of Singapore (NUS) has created the first two-photon, small-molecule fluorescent probe that can serve as a useful tool for the rapid assessment of an individual's potential risk for Parkinson's disease.
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The highly sensitive fluorescent probe can detect with high precision the activity of Monoamine Oxidase B (MAO-B), an enzyme that is found in elevated levels in patients with Parkinson's disease. The work could lead to the development of less costly, noninvasive technologies and devices to help monitor the disease's risk and progression.
Monoamine oxidases (MAOs) are enzymes that are found mainly in the human brain. Its two isoforms—MAO-A and MAO-B—work together to help maintain the balance of neurotransmitters in the brain. But when the enzymes are over-activated, the brain produces an excessive level of neurotoxic byproducts, causing neuronal dysfunctions that lead to psychiatric disorders and neurodegenerative diseases. In the case of Parkinson's disease, it is found that the expression of MAO-B, but not MAO-A, is significantly enhanced in the brain of patients and increases with age.
The high MAO-B activity consistently observed in patients with Parkinson's disease has been proposed as a biomarker, but there has been a lack of suitable small-molecule probes for MAO-B specific detection in live cells and tissues. Some of the existing fluorescence-based MAO-B probes require the addition of activating reagents, which can affect the properties of the enzymes and reduce the accuracy of detection, while some others are unable to distinguish precisely between MAO-B and the closely related MAO-A.
The small molecule probe designed and synthesised by the NUS team addresses these inadequacies of existing probes. Their probe is highly sensitive and can detect MAO-B specifically with greater precision. The fluorescence label on the probe also allows it to be detected via high-resolution imaging techniques in tissues and organs at depths of up to 1 mm, which enables researchers to effectively monitor the in vivo enzymatic activities of MAO-B in living systems. These were all not possible previously with the existing MAO probes.
The study also found that in patients with Parkinson's disease, MAO-B activities are present only in human B-lymphocytes (a type of white blood cell), but not in fibroblasts (cells typically found in connective tissues).
"This suggests that MAO-B activity in peripheral blood cells of a patient might serve as an accessible and economical biomarker to evaluate the potential risk of an individual for this disease," says associate professor Lim Kah Leong from the National Neuroscience Institute (Singapore) and also the Department of Physiology at the NUS Yong Loo Lin School of Medicine, who co-led the work. Presently, there is no reliable biomarker for Parkinson's disease, either at the diseased or preclinical state, except for dopamine-based positron emission tomography (PET) imaging, which is costly and requires highly specialized skills to perform.
"The probe may potentially be useful to monitor patients' response to medication," says Associate Professor Louis Tan, Senior Consultant, Department of Neurology at the National Neuroscience Institute, whose team has recently shown in a separate study that long-term use of a MAO-B inhibitor reduces the progression of early Parkinson's disease.
The probe also has no apparent toxicity in most mammalian cells, so it can be used to monitor MAO-B activities in vivo during various stages of the disease. As such, the probe can also become a useful tool to understand how Parkinson's disease progresses as well as for drug development.
The research team intends to further their research on the probe. One of their immediate priorities is to validate the effectiveness of their probe in detecting MAO-B in a larger pool of patient samples, with an aim of eventually developing the probe into a commercial test kit to monitor disease progression.
Full details of the work appear in the journal Nature Communications; for more information, please visit http://www.nature.com/ncomms/2014/140213/ncomms4276/full/ncomms4276.html.
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