Probe lights the way for Parkinson’s disease research

NUS researchers have created the first highly sensitive two-photon, small-molecule fluorogenic probe to evaluate the potential risk for Parkinson’s disease and monitor its progression. The chemical probe is a compound that fluoresces when it reacts with the Monoamine Oxidase B (MAO-B) enzyme.These findings were published in the Nature Communications journal last month.

The study found that patients with Parkinson’s disease have elevated levels of MAO-B in human B-lymphocytes (a type of white blood cell), but not in fibroblasts (cells typically found in connective tissues). Physicians can potentially track the risk of Parkinson’s disease in a patient and monitor its progress by measuring the intensity of light generated by the probe, which corresponds to the amount of MAO-B expressed.

“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,” said NUS Physiology Associate Professor Lim Kah Leong, who is also the Principal Research Scientist at the National Neuroscience Institute. He co-led the study with NUS Chemistry Professor Yao Shao Qin.

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 Monoamine Oxidase A (MAO-A) enzyme.

Parkinson’s disease is the most common neurodegenerative disorder, affecting six million people worldwide. The numbers in Singapore are comparable to the global numbers. There were 4,000 cases, with 300 new cases added each year, according to a late 2011 report in The Straits Times.

Presently, there is no reliable biomarker for Parkinson’s disease, either at the diseased or preclinical state, except for dopamine-based PET imaging, which is costly and requires highly specialised skills to perform. This innovation paves the way for the development of less costly non-invasive technologies and devices to help monitor the risk and progression of Parkinson’s disease.

The small molecule probe designed and synthesised by the NUS team addresses the inadequacies of existing probes. This probe is highly sensitive and can detect MAO-B 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 one millimetre, 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 probe also has no apparent toxicity in most mammalian cells, so it can be used to monitor in vivo MAO-B activities 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.

“Our findings for this study provide important starting points for using small molecule imaging techniques to explore MAO-B further at the organism level, and, in fact, opens up future prospects for non-invasive imaging-based diagnostic applications,” said Dr Li Lin, first author of the paper and a Research Associate in Prof Yao’s lab. Dr Li co-authored the paper with Dr Zhang Chengwu, a Post-Doctoral Fellow in Assoc Prof Lim’s laboratory.

The NUS research team intends to further its research on the probe. One of its 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 the progression of Parkinson’s disease.

The team also recently obtained a grant from the National Medical Research Council in Singapore to complete a study, within the next four years, using the probe to examine the relationship between key Parkinson’s disease-linked genes and MAO-B expression and activity to further understand the causes of the disease and illuminate the role of MAO-B in this.

This article was first published on 7 Mar 2014 in NUS News by Office of Corporate Relations at http://news.nus.edu.sg/highlights/7421-probe-lights-the-way-for-parkinson-s-disease-research