GATA-1 and GATA-2 adheres to the alpha-synuclein gene, according to PNAS paper.

Genetic mechanisms involved in blood cells also control a gene and protein that cause Parkinson’s disease (PD), according to a group of neurologists and pharmacologists.

Patients with Parkinson’s have elevated levels of a protein called alpha-synuclein in their brains. The current study found that the activity of three genes that control the synthesis of heme precisely matched the activity of the alpha-synuclein gene.

The scientists then found that the GATA-1 protein, which turns on the blood-related genes, also acted as a switch for alpha-synuclein expression, increasing its level. Finally, they demonstrated that a related protein GATA-2 was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.

Clemens Scherzer, M.D., of Harvard Medical School and Michael Schlossmacher, M.D., at the University of Ottawa previously analyzed the blood of PD patients and controls to identify genes that were active in the disease. They were surprised to notice large amounts of alpha-synuclein in the blood.

To understand what it was doing there, Dr. Scherzer’s group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene-expression pattern composed of alpha-synuclein and the heme genes. Emery Bresnick, Ph.D., a University of Wisconsin, Madison professor of pharmacology has already shown one of these genes to be a direct GATA-1 target gene.

The three investigators began work together and determined that GATA-1 directly activated the alpha-synuclein gene. That finding led to the discovery that GATA-2 is expressed in regions of the brain that are relevant to PD. They then set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.

The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it, and then directly control it. “This is not an indirect pathway; it is direct regulation of the gene,” asserts Dr. Bresnick. “This directness provides the simplest scenario for creating a therapeutic strategy.”

Drs. Bresnick, Schlossmacher, and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 gene may exist in PD patients, stimulating more production of alpha-synuclein.

The findings are published in this week’s online early edition of the Proceedings of the National Academy of Sciences.

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