Heme Gene Controller May Be a New Path To Treatment of Parkinson Disease

ARTICLE IN BRIEF

Heme metabolism viewed in immature red blood cells may provide a new window into the role of alpha synuclein and iron storage in Parkinson disease, investigators report.

Alpha-synuclein, the protein that accumulates in the brain as dopamine-containing cells die, and disordered iron storage, have both been implicated as possible causes of Parkinson disease (PD).

But a new report theorizes that the two processes converge in the immature red blood cell. Surprisingly, investigators found that alpha-synuclein is expressed in high amounts in red blood cells, where its expression is tightly correlated to that of the heme processing genes, according to a paper in the Aug. 5 edition of The Proceedings of the National Academy of Sciences. The scientists also identified a controller for this coordinated response.

Figure. Dr. Clemens ...

We found what we think is a molecular switch to turn alpha-synuclein expression up or down, said Clemens R. Scherzer, MD, a neurologist and researcher at Brigham and Women's Hospital, and the Center for Neurologic Diseases at Harvard Medical School in Boston. This switch may be important because now you can start looking for drugs that might reduce production of alpha-synuclein.

MASTER SWITCH PROPOSED

The switch is the GATA transcription factor, a regulator that appears to coordinate heme synthesis and insertion into the hemoglobin molecule of erythrocytes. Thus alpha-synuclein appears to be part of an iron metabolic pathway that opens a window to modeling the disorder in human red blood cells

We really stumbled upon this while seeking biomarkers for the disease in blood, Dr. Scherzer said. We were stunned to see more than three times higher levels of synuclein in erythroid cells than in the brain. He noted that his collaborator, Michael Schlossmacher, MD, now at the University of Ottawa, independently found around the same time evidence that alpha-synuclein might be produced in the red blood cell progenitors.

Out of thousands of genes expressed in blood, a small set appeared whose activity was tightly matched to alpha-synuclein levels. Three were heme metabolism genes. This suggested that a master regulator might be controlling both alpha-synuclein gene expression and the heme metabolism genes.

GATA-1 and its related transcription factor GATA-2 overlap in ability to induce the heme pathway, but it is GATA-2, produced in dopamine neurons, that can guide neuron formation and development in the brain. Collaborating with GATA expert Emery Bresnik, PhD, a pharmacologist at the University of Wisconsin School of Medicine and Public Health, the Boston and Ottawa researchers silenced GATA-2 in a dopamine producing, neuroblastoma cell line, which decreased concentration of the message for production of alpha- synuclein by 28 percent, and of the protein itself by 46 percent. They wrote this is a biologically plausible decrease, suggesting a role for the transcription factor in the disorder.

POSSIBLE DISEASE CLUE

It is an exciting clue from a pathobiologic standpoint, said Dr. Scherzer, as Parkinson disease is linked to abnormal deposits of both alpha-synuclein and iron, particularly in the substantia nigra.

Who would have thought it, red blood cells, said J. William Langston, MD, chief executive officer and scientific director of the Parkinson's Institute in Sunnyvale, CA. It is an important paper because it gives us one more avenue to pursue, Dr. Langston said. There is a huge race on to try to alter synuclein levels or expression and they may have discovered a new approach. The more strategies we have, the better.

Dr. Langston noted that investigators reported in 2003 in Science that there are families that carry a triplication of the gene on one allele, so that they make twice as much alpha-synuclein and get a much more aggressive form of the disease, with early onset, more rapid progression, and higher incidence of dementia.

These cases were seminal, he said, in that they proved for the first time that too much normal synuclein could replicate all of the pathological features of PD. It is not clear that synuclein is the cause of the sporadic disease. So the strategy to suppress the protein may not be safe for all cases.

If you suppress synuclein in a normal person, or in idiopathic PD, would that be okay? Dr. Langston cautioned.

Robert L. Nussbaum, MD, Holly Smith Distinguished Professor in Medicine and chief of the Division of Medical Genetics in the department of medicine and a member in the Institute of Human Genetics at the University of California-San Francisco, collaborated in efforts to identify the mutation in the gene encoding alpha-synuclein as a link to inherited Parkinson disease. He said that alpha-synuclein transcripts are elevated in sporadic Parkinson disease, but said several new questions need to be explored: Is less being degraded or is more being made? What role does GATA-2 play in this - are there negative regulators that block its action, and what happens to GATA-2 during free radical stress, or any of the chemical exposures that induce Parkinson disease?

Dr. Nussbaum called the link with iron metabolism tenuous, but noted, it is possible that alpha-synuclein plays a subtle role in heme biosynthesis or erythropoiesis. He said there is anecdotal evidence for increased iron stores in the affected parts of the brain in Parkinson disease, even though no hemoglobin is made in neurons.

Still unknown is why there is so much alpha-synuclein in the blood cells, an observation Dr. Nussbaum said his team made six or seven years ago, and also in platelets, although the latter cell was not addressed in the report. We don't know what it is doing there, or even what it is doing in brain, he noted, though there is some hint for a role in neuronal vesicle traffic. It's a good use of genomic approaches to use coordinated gene expression to find factors involved in regulation, he said about the report, and it's a fine contribution. •