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Genetic Risk Factor for Parkinsonís Linked to Increased Alpha-Synuclein

Researchers have shed light on a mystery about the relationship between a gene called GBA and Parkinson’s disease (PD). Carriers of mutations in this gene are at a higher risk for Parkinson’s for unknown reasons. Researchers found that mutations in the gene lead to an accumulation of alpha-synuclein protein in brain cells, the hallmark of the disease. The research was published in the April 6 online edition of Annals of Neurology.

In recent years, scientists discovered that mutations in a gene known as glucocerebrosidase or GBA, are the most common genetic risk factor for Parkinson’s.  People who carry mutations in one copy of the GBA gene may have up to a five times the normal risk of developing PD.  In addition, mutations in GBA increase the risk of another neurodegenerative disease, dementia with Lewy bodies (DLB).  Mutations in both copies of a person’s GBA gene cause the rare disorder known as Gaucher’s disease.  But the role of this gene in the development of Parkinson’s remained unknown.

A new study led by Valerie Cullen, Ph.D., and Michael G. Schlossmacher, M.D., and their colleagues at both Harvard Medical School in Boston, MA, and the University of Ottawa in Ottawa, Canada, set out to understand the molecular pathways connecting GBA mutations with increased alpha-synuclein. They used a range of laboratory methods to study nerve cells grown in culture that had GBA mutations as well as mice carrying these mutations.


  • The researchers established, in experiments with nerve cells grown in the laboratory, that alpha-synuclein accumulated in cells with GBA mutations.
  • Biochemical studies showed that GBA mutations prevented cells from efficiently breaking down and removing alpha-synuclein.
  • In mice with GBA mutations, alpha-synuclein levels increased in brain cells as the mice got older.


What Does it Mean?

While most carriers of GBA mutations do not develop Parkinson’s disease, carrying a mutation increases the risk for Parkinson’s. This current research showed that the mechanism of this increased Parkinson’s risk is mediated by alpha-synuclein protein build up in nerve cells, including those that help control the body’s movements.  Clusters of alpha-synuclein in these cells are linked to the cell death responsible for PD.

Better understanding of the biology of Parkinson’s may help scientists develop drugs that will modify PD progression. Drugs already are under development that target GBA in order to treat Gaucher’s disease. Understanding the link between GBA and PD may  prove useful in designing drugs against Parkinson’s and Lewy body dementia.

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Source Date: Apr 20 2011