Published on June 11, 2014

On the PARKINSON'S DISEASE FOUNDATION website

http://www.pdf.org/en/science_news/release/pr_1402498748

Researchers have apparently identified a therapeutic approach to Parkinson's disease, after examining tissue samples from people suffering from a rare hereditary disease known as Gaucher's disease, who have a high level of risk of developing Parkinson's disease. Their findings, published in the May 2014 issue of the journal BRAIN, suggested that a drug called AMBROXOL may help treat certain forms of Parkinson's disease.

Gaucher disease patients have mutations in both copies of the GBA gene. In the disease, the enzyme created by this gene (GLUCOCEREBROSIDASE), is unable to do its job - removing fatty deposits from certain cells in certain organs. Carriers of Gaucher disease (people with one copy of the gene mutation), do not show Gaucher disease symptoms, but they have shown an increased risk of developing in Parkinson's disease.

The researchers still do not know how the mutations in GBA contribute to the increased risk of Parkinson's disease.

To find an answer to this question, a group of researchers led by Dr. Antony Shapira from the University of London in the United Kingdom collected skin samples from 5 Gaucher patients, four carriers (with one copy of the mutation) who were also patients with Parkinson's disease, two who were not patients with Parkinson's disease and three healthy (control). The researchers treated the skin tissue cells with a drug called: AMBROXOL, which is known to accelerate the activity of the GLUCOCEREBROSIDASE enzyme and examined the results.

Results

• As expected in skin cells from Gaucher disease, the researchers found that the GLUCOCEREBROSIDASE enzyme was significantly less active than in the other treatment groups - in fact it was 95% lower compared to its activity in healthy people.
• The activity of the enzyme in Gaucher disease carriers, both in Parkinson's disease patients and in those who do not have Parkinson's disease, was about 60% of normal.
• Skin cells from people who were sick or women (one copy, or two copies of the mutation in the GBA gene) showed more signs of stress, which can lead to cell damage and even death, compared to the control.
• In the skin cells of all groups, the drug AMBROXOL increased the activity of the enzyme GLUCOCEREBROSIDASE and also its products.
• Skin cells that had the mutation in the GBA gene and were treated with AMBROXOL looked healthier and showed less signs of stress.
• In nerve cells, AMBROXOL lowered the levels of a certain protein ALPHA SYNUCLEIN that accumulates in Parkinson's patients.

What do the results mean?

A better understanding of the biological links between Gaucher's disease and Parkinson's disease could help us develop a new treatment approach for Parkinson's disease. The findings from the current trial imply that AMBROXOL, a drug that is on the market in Europe, should be tested as a drug for Parkinson's disease, probably in those with the mutated GBA gene, Gaucher's disease and hopefully also in general Parkinson's disease.

Current research indicates that Gaucher's and Parkinson's diseases can be related to cell turnover - the ability of cells in the body to recycle waste. In Gaucher's disease when there is a mutation in the GBA gene, the cells are unable to eliminate fat waste properly. Similarly in Parkinson's patients, the cells are probably not able to effectively dispose of protein debris such as that of ALPHA SYNUCLEIN.

The study shows that AMBROXOL may clear the sediment. In this case, the drug works by increasing the amount of the GLUCOCEREBROSIDASE enzyme and increasing its activity level. Cells with an increased level of GLUCOCEREBROSIDASE activity appeared healthier and could better dispose of protein waste such as ALPHA SYNUCLEIN.

While AMBROXOL is already on the market for the treatment of other diseases, the results of the current studies show only a slight improvement in the activity of the enzyme and further studies will be required. It will be important to study the additional cellular effects of the GBA and AMBROXOL mutations in neurons and in animal models of Parkinson's disease.

bibliography

McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AHV (2014) Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 137:1481–1495. DOI: 10.1093/brain/awu020 http://dx.doi.org/10.1093/brain/awu020