In a surprise finding, a study by researchers from NorthShore University HealthSystem and the Mayo Clinic provides genetic and clinical evidence that some new Parkinson’s disease therapies may actually accelerate disease progression and increase the risk of becoming physically incapacitated and demented.
Specifically problematic are those therapies that target the expression of alpha-synuclein – a protein whose function in the healthy brain is unknown, but is a major constituent of Lewy bodies, protein clumps that are the pathological hallmark of Parkinson’s disease.
Since its discovery as a cause of familial Parkinson’s disease nearly 20 years ago, alpha-synuclein has been the focus of intensive efforts by researchers working to definitively characterize the protein’s role in idiopathic Parkinson’s disease and its potential as a target for neuroprotective therapies.
This news is particularly concerning given that a vaccine targeting alpha-synuclein in Parkinson’s patients is currently undergoing clinical testing in Parkinson’s patients and a number of molecules that target the protein for reduction are in advanced stages of preclinical development. The vaccine candidate, from Austrian biotech AFFiRiS, works by binding to alpha-synuclein and subsequently clearing it from the brain.
As of January 2012, The Michael J. Fox Foundation had invested over $47 million in projects targeting alpha-synuclein.
“Our research suggests that 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 Demetrius M. Maraganore, MD. “We believe it is our responsibility to release these data because this type of treatment may have long-term harmful effects.”
“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,” adds study author Katerina Markopoulou, MD, PhD, a neurologist at NorthShore.
The researchers followed 1,098 Mayo Clinic patients for nearly 15 years and sequenced the patients’ DNA to determine the presence of gene variants that regulate how much alpha-synuclein protein is made. They also studied the association of these gene variants with patients’ survival free of severe motor and cognitive disabilities.
Patients who had reduced expression of alpha-synuclein had a 23% greater risk of becoming wheelchair-dependent or developing dementia.
If replicated, the findings, presented Wednesday at the annual meeting of the American Academy of Neurology will have profound implications regarding therapies under development for Parkinson’s disease.
Interestingly, this is not the first time alpha-synuclein has been challenged. SRxA’s Word on Health has discovered literature from 2008 showing that there are people with Parkinson’s Disease that have no accumulation of alpha-synuclein, and people who have accumulated alph-synuclein who do not have Parkinson’s Disease. In autopsy studies, 30%-55% of elderly subjects with widespread alpha-synuclein pathology were found to have no definite neuropsychiatric symptoms; yet when large amounts of alpha-synuclein had fewer patients were found to have Parkinson’s Disease. These authors concluded that much of the Parkinson’s Disease research was being done without having any scientific or factual basis.
Looks like people should have listened!
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