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Study counters Parkinson's disease gene theory

25 March 2013
Appeared in BioNews 698

An experimental approach to treating Parkinson's disease may need to be reconsidered following evidence suggesting that it may make patients worse.

Alpha-synuclein is a protein that is a focus for research as it is a major component of Lewy bodies - clumps of protein that develop in nerve cells in the brain and that are found in all Parkinson's disease cases.

Mutations in the alpha-synuclein gene have been identified as a cause of familial Parkinson's disease for a very small minority of patients and the protein was thought by many to play role in the development of the disorder more generally.

Several pharmaceutical companies, including Alnylam Pharmaceuticals, who helped fund this research, have been developing drugs designed to reduce levels of alpha-synuclein. A vaccine targeting alpha-synuclein is currently in early clinical trials.

In the study, researchers in the USA followed 1,098 Parkinson's disease patients for up to 15 years. Patients' DNA was sequenced to determine the presence of gene variants that control how much alpha-synuclein nerves produce. They then looked at the association of these gene variants with patient outcomes.

As expected, high levels of alpha-synuclein increased the risk of developing Parkinson's disease. But patients who had the disease and had lower levels of alpha-synuclein were more likely to suffer more severe motor symptoms, such as tremor and impaired movement, and decline in cognitive skills.

Patients who produced the least alpha-synuclein had a 23 percent greater risk of becoming wheelchair-dependent or developing dementia than other patients.

'Our research suggests therapies that seek to suppress alpha-synuclein in Parkinson's disease may actually accelerate the disease process and increase the risk for developing severe physical disability and dementia', said lead author Dr Demetrius Maraganore, chairman of neurology at NorthShore University Health System.

So far the research has only been presented at a conference, the American Academy of Neurology Annual Meeting, and not in a peer-reviewed journal. However, Dr Maraganore says, 'it is our responsibility to release these data because [experimental alpha-synuclein-countering treatments] may have long-term harmful effects'.

Previous research by the same laboratory group showed that people who inherit a DNA mutation increasing alpha-synuclein production have a 50 percent greater chance of developing Parkinson's disease than those that do not.

Dr Maraganore suggests that alpha-synuclein is a protein that is critical for healthy nerve function, so that too little or too much at different points in time can be harmful.

Genetic Evidence for a Dual and Opposing Effect of alpha-Synuclein Expression in Preclinical Versus Clinical Parkinson's Disease
American Academy of Neurology |  20 March 2013
Genetic Evidence That New Therapies Targeting Parkinson's Disease May Cause Harm
Science Daily (press release) |  20 March 2013
Parkinson’s Patients May Be Harmed by Novel Treatment
Bloomberg News |  21 March 2013
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