- Parkinson’s disease is the second most common form of neurodegenerative disease after Alzheimer’s disease. In an aging population, the number of people diagnosed with PD is set to rise.
- Existing treatments aim to alleviate symptoms but do not prevent progression.
- A recent study has shown that tiny antibodies — called nanobodies — produced by llamas could hold potential for the development of future treatments.
Parkinson’s disease (PD) starts when nerve cells in the part of the brain that controls movement stop working properly or die.
These cells stop producing the chemical dopamine, which is crucial for regulating the cell signaling responsible for movement. This produces the symptoms of PD. Exactly why these cells die is still unknown.
Dr. Beckie Port, head of research communications and engagement at Parkinson’s UK, told Medical News Today, “With more than 40 symptoms, Parkinson’s can have a significant impact on daily life, and those living with the condition need better treatments urgently.”
Diagnosis of the disease is not straightforward. There is no specific laboratory test, and diagnosis is usually based on medical history and examination. Often people dismiss the early signs of PD as part of aging.
Scientists think that Parkinson’s disease may happen due to a combination of environmental and genetic factors. Although there is no one specific gene that can be said to cause PD, there are several genes that appear to play a part.
One of these genes is called LRRK2. This codes for a protein called leucine-rich repeat kinase 2 (LRRK2). Mutations in the gene are involved in the inherited form of PD. Overactivation of the gene also
Current drug development research has focused on LRRK2 kinase inhibitors that interfere with the binding of the substrates of the protein, but there are concerns about potential side effects. New research has found a way to inhibit the LRRK2 protein using a different mechanism, with potentially fewer side effects.
A recent study was led by Prof. Wim Versées, Ph.D. at the Vrije University of Brussels and theFlanders Institute for Biotechnology in Belgium.
The scientists found that nanobodies — small, antibody-like molecules — can target LRRK2. Not only can the nanobodies block the action of the protein, but some of them can also selectively inhibit certain activities of the protein while leaving others to continue. Their findings appear in the journal PNAS.
Dr. James Beck, Ph.D., chief scientific officer of the Parkinson’s Foundation, told Medical News Today: “This is a very creative set of experiments that utilize a unique approach to differentially modulating the activity of the LRRK2 protein.”
“Before,” he continued, “scientists could only turn the LRRK2 protein on or off. However, these results allow for the precise modulation of LRRK2 activity. This is like moving from a stereo that only had an on-off switch to one that now has a full suite of controls to fine-tune the sound.”
Nanobodies are a type of small antibody fragment generated by llamas and camels. Nanobodies have a number of differences from human antibodies.
As they are smaller and simpler than human antibodies, nanobodies are easier to produce in the laboratory. Scientists can make them in bacterial cells that are much cheaper to grow and maintain than the mammalian cells required for antibody production.
To generate the nanobodies that bind to LRRK2, the research team — which also included scientists from Germany, The Netherlands, and the United States — immunized different llamas with LRRK2 using slightly different strategies. This generated 168 families of antibodies from the llamas’ blood samples.
The team then selected 10 of the most effective nanobodies and ran a series of laboratory tests to characterize these in detail. They were able to classify the nanobodies into five categories, each of which has a different mode of action.
Prof. Versées told MNT:
“[W]e were most surprised by our large repertoire of nanobodies that can affect LRRK2 activity in many different ways. Since PD is linked to increased LRRK2 activity in brain cells (neurons) of patients, those inhibitory nanobodies are of particular interest.”
“While our results are very exciting and promising, we now plan follow-up experiments to characterize how exactly these nanobodies achieve their inhibitory activities using this wide variety of different mechanisms. In addition, […] a next step would be to test them in relevant neuronal cells and in vivo in appropriate model organisms.”
Dr. Beck said: “These new nanobody modulators are only tools. They are not designed to be used in people, but can be used to help identify new drugs that could work in the same manner. More work needs to be done but this will set the stage for a different approach toward creating a therapy for Parkinson’s disease.”
“One current challenge in using Nanobodies (or proteins in general) to treat neurological disorders is that they need to reach and enter the correct cells in the brain,” Prof. Versées added.
“An approach to achieve this is via gene therapy. While the latter currently still comes with large technological challenges and high costs, the field of gene therapy is evolving rapidly, and we can thus hope that it would offer new opportunities in the years to come.”