Increasing the amount of glucocerebrosidase (GBA enzyme) in the brain may help to treat Parkinson's disease (PD) and other similar disorders, according to research published online January 7 in the Proceedings of the National Academy of Sciences. The enzyme, which clears fatty deposits from cells in the brain and other organs, may also help keep harmful deposits of the protein alpha-synuclein from accumulating in the brain.
Previous observations suggested a link between a deficiency in the GBA enzyme and PD. For example, people with PD typically have lower amounts of GBA enzyme in their brains. Some people living with PD also have mutations in the GBA1 gene, which makes this enzyme and causes Gaucher's, a disease which can include PD-like symptoms.
Researchers led by Richard Sidman, M.D., at Harvard Medical School and S. Pablo Sardi, Ph.D., at Genzyme, a biotechnology company, wondered whether boosting GBA enzyme levels might prevent the harmful clumping of alpha-synuclein in the brain that kills dopamine-producing brain cells, leading to PD symptoms. They studied the concept, using two mouse models: mice with symptoms of Gaucher's disease and other mice with PD-like symptoms. Researchers treated mice with gene therapy - an injection of healthy copies of the GBA1 gene. This treatment caused them to produce high levels of GBA enzyme in their brains. Six months later, the researchers observed the impact on their brains and symptoms.
Six months after the gene therapy treatment, the mice with symptom's of Gaucher's disease, had reduced fatty deposits in the brain and fewer clumps of misfolded alpha-synuclein and other proteins associated with nuerological disorders. The treatment also restored the impaired memory of these mice to normal levels.
Like people with PD, mice treated to have PD-like symptoms had lower amounts of active GBA enzyme than normal mice. Mice with the highest levels of alpha-synuclein had the lowest levels of GBA enzyme.
In the PD mice, the gene therapy treatment decreased the amount of free alpha-synuclein in the brain, but not of alpha-synuclein clumps.
What Does It Mean?
This study adds to existing evidence that a deficiency in the GBA enzyme may contribute to PD symptoms. It also suggest that fixing this deficiency could be therapeutic.
Scientists still are not sure exactly how a deficiency in the GBA enzyme could cause or contribute to PD. It is possible that the enzyme normally clears out excess alpha-synuclein, that it helps the protein fold properly to prevent its clumping together, or that is breaks up protein clumps. Further studies are needed to determine the precise role of the enzyme in PD.
As these medications are developed, they would need to be extensively tested for safety and efficacy in treating people with Parkinson's.
Reference: Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, Bu J, Sweet L, Passini MA, Dodge JC, Yu WH, Sidman RL, Cheng SH, Shihabuddin LS (2013) Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proceedings of the National Academy of Sciences:1-6.