You might recall that the chemical alpha-synuclein is an aggregate that appears to be a proximate cause of Parkinson's disease (and like many biochemical aggregates, its buildup is slowed by the practice of calorie restriction). Researchers are delving deeper into the chain of mechanisms:
Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.
The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.
The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein -- GATA-2 -- was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.
Researchers are taking a similar tack to that of mainstream Alzheimer's research now that a greater understanding of alpha-synuclein exists. Get rid of the aggregate, in other words:
"Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focused on ways to get rid of too much 'bad' alpha-synuclein in Parkinson patients' brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front."
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," says Bresnick. "This directness provides the simplest scenario for creating a therapeutic strategy."
The problem with influencing the production side is, of course, that everything in our biochemistry has many different roles. It's next to impossible to alter any gene or mechanism without causing unwanted side-effects. This is a strong incentive to focus primarily on cleaning up aggregates rather than re-engineering our metabolism, if those are the only two options on the table. Further options will hopefully emerge as researchers progress towards an understanding of why these mechanisms change with age. What form of known age-related biochemical damage is causing changes in GATA regulation - and thus alpha-synuclein levels - and how is it doing that?