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Targeting the shape of protein aggregates to treat Parkinson’s

Written by GK on in the category Interviews with the tags , , , .


Parkinson's disease (PD) is the second most common neurodegenerative disorder in the world. Similar to Multiple System Atrophy (MSA) and dementia with Lewy bodies (DLB), it is linked to the aggregation of a protein called alpha-synuclein. Scientists from KU Leuven, in collaboration with CNRS (Centre national de la recherche scientifique) and the UA, recently observed that pathogenesis of PD and MSA involve different types of alpha-synuclein aggregates. The results of the collaboration were recently published in Nature (1). Professor Veerle Baekelandt, neurobiologist and professor at the Laboratory for Neurobiology & Gene Therapy at KU Leuven explains why this discovery is important and gives us an update on advances in the field of Parkinson’s disease.

“When I did my masters in biology at KU Leuven I became interested in the brain in general - it was a fascinating topic. To better understand how the brain works, I did my PhD in basic neuroscience.  As a postdoc, I got the opportunity to work on Alzheimer’s. Later on, I joined a gene therapy project for neurodegenerative diseases at KU Leuven and shifted my focus to Parkinson’s disease as not many scientists were working in this field at that time,” says Baekelandt. Now she is the head of the Laboratory for Neurobiology and Gene Therapy that is collaborating with the Michael J. Fox Foundation for Parkinson's Research. Veerle focuses on the molecular pathogenesis of PD; her areas of interest include leucine rich kinase 2 (LRRK2) and alpha-synuclein. The latter is particular interest.

It’s all in the shape

Alpha-synuclein is a protein found in the human brain that that plays an important role in the functioning of neurons. However, aggregates of this protein can be harmful for the brain.

"Protein aggregates of alpha-synuclein disrupt communication between brain cells, resulting in cell death. Up to now, nobody has been able to understand how aggregates of this single protein could induce different pathologies," explains Veerle Baekelandt.

Several types of aggregates, called strains, can be formed. The two major strains are cylinder-shaped fibres and broad ribbons. As described in the latest Nature publication , each strain causes a different pathology when injected into a rat’s brain. While the cylindrical fibers induce PD, the ribbons cause MSA symptoms. “We are now investigating the alpha-synuclein aggregates from PD and MSA patients to confirm the correlation of their shape to the pathology seen in humans. Once we can prove this correlation, we will try to develop therapies that are able to specifically target one of the shapes of the alpha-synuclein aggregates,” says Baekelandt. “This could be possible by using small molecules or antibodies which are able to specifically recognize the protein arrangement. The way to eliminate the aggregates might be different for PD and MSA patients.”

No biomarker, no diagnosis

“At the moment it is impossible to visualize the shape of the alpha-synuclein aggregates in the brain of living patients. However, in theory, diagnosis could be made using PET scans, using a technique similar to how Alzheimer’s patients are diagnosed. There are several radio-labeled tracers that bind to beta-amyloid plaques in the brains of Alzheimer patients. In brain PET scans the tracers show the buildup of the amyloid proteins. “If you could develop an antibody and label it with a PET tracer, you could do PET imaging of the PD patients brain.” 

Nowadays, the idea of intercepting a neurodegenerative disease before clinical symptoms develop is very popular. The first step in fighting this disease before neurodegenerative symptoms occur is effective diagnostic screening. “We still need to find a reliable biomarker to allow for early detection of PD. Such a biomarker would allow us to start treatment early,” explains Veerle. “Currently, only patients with a rare genetic form of PD can be diagnosed before the clinical onset of the disease. We also need a test to identify PD in at-risk populations.”

A breakthrough in PD therapy is just a matter of time

There are several options to effectively address PD, such as small molecule drugs that are able to block alpha-synuclein aggregation, gene therapy to repair faulty gene expression and stem cell therapy to replace the damaged neurons in the patient’s brain. “I think the most promising options are the drugs that target the aggregation of alpha-synuclein with small molecule drugs or antibodies. There are also very interesting ongoing clinical trials in gene therapy where researchers are trying to counteract the loss of dopamine by introducing the genes of the enzymes that produce L-dopa in the patient’s brain. It is like supplementing L-dopa from within the brain. Another option is supplying neuro-protective growth factors to stop neuron loss. However, the most promising solution, currently being intensely explored, would be to directly target the genes that cause the disease: alpha-synuclein, LRRK2 and parkin,” elaborates Veerle Baekelandt.

I really believe that an effective therapy for Parkinson’s disease will become available for patients. It may take 5 or 10 years, but with the huge investments and effort of researchers around the world, success is inevitable.

 

Reference

Peelaerts, Wouter, L. Bousset, Anke Van der Perren, A. Moskalyuk, R. Pulizzi, M. Giugliano, Chris Van Den Haute, R. Melki, and Veerle Baekelandt. "α-Synuclein strains cause distinct synucleinopathies after local and systemic administration" Nature (2015)

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