3/20/2014 NorthShore University HealthSystem (NorthShore) researchers have published a study that reports genetic and clinical findings cautioning that therapies targeting the expression of alpha-synuclein —  a gene whose function is involved in the development and progression of Parkinson’s disease — may accelerate disease progression and increase the risk of physical incapacitation and dementia. If replicated, the findings may have significant implications for the treatment of Parkinson’s disease.

“Our research suggests that therapies 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,” says lead author Demetrius Maraganore, M.D., Ruth Cain Ruggles Chairman, Department of Neurology at NorthShore. “We believe it is our responsibility to publish these findings in a peer-reviewed journal, because these types of treatments may have unanticipated long-term effects. Our findings require replication.”

The alpha-synuclein protein, encoded by the gene that Maraganore and colleagues studied, is a major component of Lewy bodies — the characteristic brain cell abnormality that occurs in all cases of Parkinson’s disease. Since its discovery as a cause of familial Parkinson’s disease nearly 20 years ago, the alpha-synuclein gene and protein have been the focus of intensive research efforts to characterize their role in Parkinson’s disease, as well as their potential as targets for neuroprotective therapies. Because increased alpha-synuclein levels have been linked with the development of Parkinson’s disease, multiple efforts to develop treatments to reduce its levels in the brain are under development.

“For the first time we observed that while over-expression of alpha-synuclein increases the risk for developing Parkinson’s disease, conversely, under-expression is associated with worse motor and cognitive outcomes after the disease starts,” says first author Katerina Markopoulou, M.D., Ph.D., a neurologist at NorthShore. “This raises concerns about the efficacy of therapies designed to reduce alpha-synuclein expression in Parkinson’s disease.”

The researchers followed 1,098 patients for nearly 15 years (median: eight years), and sequenced the patients’ DNA to determine the presence of gene variants that regulate how much alpha-synuclein protein is made. They studied the association of these gene variants with survival free of severe motor and cognitive disabilities. Patient outcomes were measured by telephone interviews.

The researchers found that patients who had the reduced expression genotype had a ~25 percent greater risk of becoming wheelchair-dependent or developing dementia.  The investigators also observed similar unanticipated genetic associations (reduced alpha-synuclein genotype with worse motor and cognitive outcomes) in a familial form of Parkinson’s disease.

“This is the first large genetic association study of alpha-synuclein and motor and cognitive outcomes in Parkinson’s disease,” said Dr. Maraganore. “If replicated, this research may change or modify the treatment paradigm focused on alpha-synuclein reduction for Parkinson’s disease.”

The study was published in the Parkinsonism and Related Disorders Journal.

The study was funded by the National Institutes of Health, Alnylam Pharmaceuticals Inc., and Medtronic Inc.