Drugs that target retromer pathway could help prevent or treat Parkinson's

Published on February 9, 2013 at 4:31 AM · No Comments

Columbia University Medical Center (CUMC) researchers have identified a protein trafficking defect within brain cells that may underlie common non-familial forms of Parkinson's disease. The defect is at a point of convergence for the action of at least three different genes that had been implicated in prior studies of Parkinson's disease. Whereas most molecular studies focus on mutations associated with rare familial forms of the disease, these findings relate directly to the common non-familial form of Parkinson's. The study was published today in the online edition of the journal Neuron.

The defective pathway is called the "retromer" pathway, in part because it can guide the reutilization of key molecules by moving them back from the cell surface to internal stores. In this study, defects in the retromer pathway also appear to have profound effects on the cell's disposal machinery, which may explain why Parkinson's disease brain cells ultimately accumulate large protein aggregates. The trafficking defects associated with Parkinson's can be reversed by increasing retromer pathway activity, suggesting a possible therapeutic strategy. No current therapies for Parkinson's alter the progression of the disease.

The researchers also found evidence that, even in unaffected individuals who simply carry common genetic variants associated with an increased risk of Parkinson's disease, these molecular changes are at work. This supports the notion that early treatment approaches will be important in tackling Parkinson's disease.

"Taken together, the findings suggest that drugs that target the retromer pathway could help prevent or treat Parkinson's," said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC.

In recent years, through genome-wide association studies (GWAS), researchers have identified about 10 common genetic variants that appear to have small effects on the risk of non-familial Parkinson's, However, it has been hard to delve deeper into the impact of these variants. "When you look at patient brain tissue at autopsy, it's usually too late — all the critical dopamine neurons are long gone and the damage has been done," said Dr. Abeliovich.

In the current study, Dr. Abeliovich and his CUMC colleagues used an unusually broad array of approaches — including analyses of Parkinson's disease-associated genetic variations, patient brain tissue, in vitro tissue culture studies of brain neurons, and fruit fly (Drosophila) models that harbor genetic variants related to those associated with Parkinson's disease.

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