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Gaucher Disease Points Way to Possible New Treatment for Parkinsonís

Researchers may have identified a novel therapeutic approach to Parkinson’s disease (PD) by examining tissue samples from people with a rare genetic disorder known as Gaucher disease (GD) who have an increased risk of PD. Their findings, published in the May 2014 issue of the journal Brain, suggest that a medicine called ambroxol might help treat some forms of PD.

People with Gaucher disease have mutations in both copies of a gene known as GBA. In the disease, the enzyme produced by this gene (glucocerebrosidase), is unable to do its job of clearing out fatty deposits in certain cells and organs. Carriers of Gaucher (people with only one mutated copy of the gene) do not show any symptoms of the disease, but have been shown to have an increased risk of developing PD.

Scientists do not yet understand how mutations in the GBA gene contribute to PD risk. To help answer this question, researchers led by Anthony Schapira, M.D., D.Sc., F.R.C.P., at University College London in the United Kingdom, removed and examined skin cells from five people with Gaucher, four carriers (those with just one mutated copy of GBA) who also had PD, two carriers without PD, and three people without GBA mutations or PD (controls). They then treated the cells with a medicine called ambroxol which is known to boost the activity of the glucocerebrosidase enzyme and observed the effects.


  • As expected, in the skin cells of people with Gaucher disease, researchers found that the enzyme glucocerebrosidase was significantly less active than in other groups — in fact, it was reduced by 95 percent compared to healthy controls.  
  • The enzyme activity in Gaucher carriers, both with and without PD, was about 60 percent of normal. 
  • Cells from people with Gaucher and carriers (people with one or two mutated copies of GBA) showed more signs of stress, which can lead to cell damage or death, than controls. 
  • In cells from all groups, the drug ambroxol increased the activity of the enzyme glucocerebrosidase and also increased its production.
  • Cells with GBA mutations, which were treated with ambroxol appeared healthier and showed fewer signs of stress.
  • In neuronal cells, ambroxol reduced the levels of a certain protein, called alpha-synuclein, which is known to accumulate in PD.

What Does It Mean?

Better understanding of the biological connection between Gaucher disease and PD may help us to develop new treatment approaches for PD. Findings from the current study suggest that ambroxol, a drug already on the market in Europe should be studied as a treatment for PD, possibly in those who carry mutations in the Gaucher gene (GBA), but hopefully in people with PD generally.

The current study suggests that Gaucher and PD may both be linked to cellular recycling — the ability of cells in the body to recycle waste. In Gaucher disease, when there are mutations in the GBA gene, the cell is unable to properly dispose of fatty deposits. Similarly, in PD, cells may be unable to effectively dispose of troublesome proteins like alpha-synuclein.  

The study shows that ambroxol may possibly “clear the drains.” In this case, the drug does so by increasing the amount of the enzyme glucocerebrosidase, and increasing its activity level. Cells with increased glucocerebrosidase activity looked healthier and were able to better dispose proteins such as alpha-synuclein.

While ambroxol is a medication already on the market for other health conditions, these laboratory studies provided only modest improvements of enzyme activity and will still need to be confirmed. It will be important to further study the cellular effects of GBA mutations and of ambroxol in neuronal and animal models of PD.  

Reference: McNeill A, Magalhaes J, Shen C, Chau K-Y, 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

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Source Date: Jun 11 2014