Researchers at the University at Buffalo have discovered how mutations in the parkin gene cause Parkinson's disease, which afflicts at least 500,000 Americans and for which there is no cure. The results are published in the current issue of Nature Communications.
The researchers reveal potential new drug targets for the disease as well as a screening platform for discovering new treatments that might mimic the protective functions of parkin. They have applied for patent protection on the screening platform.
“This is the first time that human dopamine neurons have ever been generated from Parkinson's disease patients with parkin mutations,” says Jian Feng, professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and the study's lead author.
As the first study of human neurons affected by parkin, the UB research overcomes a major hurdle in research on Parkinson's disease and on neurological diseases in general. The problem has been that human neurons live in a complex network in the brain and thus are off-limits to invasive studies, Feng explains. “Before this, we didn't even think about being able to study the disease in human neurons,” he says. “The brain is so fully integrated. It's impossible to obtain live human neurons to study.”
But studying human neurons is critical in Parkinson's disease, Feng explains, because animal models that lack the parkin gene do not develop the disease; thus, human neurons are thought to have “unique vulnerabilities.” “Our large brains may use more dopamine to support the neural computation needed for bipedal movement, compared to quadrupedal movement of almost all other animals,” he says.
Since in 2007, when Japanese researchers announced they had converted human cells to induced pluripotent stem cells (iPSCs) that could then be converted to nearly any cells in the body, mimicking embryonic stem cells, Feng and his UB colleagues saw their enormous potential. They have been working on it ever since. “This new technology was a game-changer for Parkinson's disease and for other neurological diseases,” says Feng. “It finally allowed us to obtain the material we needed to study this disease.”
In this latest research the team “reverse engineered” human neurons from human skin cells taken from four subjects: two with a rare type of Parkinson's disease in which the parkin mutation is the cause of their disease and two healthy subjects who served as controls. “Once parkin is mutated, it can no longer precisely control the action of dopamine, which supports the neural computation required for our movement,” says Feng.
The UB team also found that parkin mutations prevent it from tightly controlling the production of monoamine oxidase (MAO), which catalyzes dopamine oxidation. “Normally, parkin makes sure that MAO, which can be toxic, is expressed at a very low level so that dopamine oxidation is under control,” Feng explains. “But we found that when parkin is mutated, that regulation is gone, so MAO is expressed at a much higher level. The nerve cells from our Parkinson's patients had much higher levels of MAO expression than those from our controls. We suggest in our study that it might be possible to design a new class of drugs that would dial down the expression level of MAO.”
He notes that one of the drugs currently used to treat Parkinson's disease inhibits the enzymatic activity of MAO and has been shown in clinical trials to slow down the progression of the disease. In 10 percent of Parkinson's cases, the disease is caused by mutations of genes, such as parkin: the subjects with Parkinson's in the UB study had this rare form of the disease. “We found that a key reason for the death of dopamine neurons is oxidative stress due to the overproduction of MAO,” explains Feng. “But before the death of the neurons, the precise action of dopamine in supporting neural computation is disrupted by parkin mutations. This paper provides the first clues about what the parkin gene is doing in healthy controls and what it fails to achieve in Parkinson's patients.”
“The study has discovered how mutations of parkin disrupt an essential function of human midbrain dopaminergic neurons - the coordinated utilization of dopamine as a neurotransmitter and the control of dopamine toxicity,” the authors write. “Further studies are needed to address why nigral dopaminergic neurons, in comparison with other types of dopaminergic neurons, are particularly vulnerable in Parkinson's disease and how parkin protects against these vulnerabilities.”
Dr Michelle Gardner, research development manager at Parkinson's UK, said the study was particularly exciting because it provided a new way to investigate this genetic form of Parkinson's. “Parkinson's UK funded research has already shown that parkin plays a key role in how Parkinson's develops in the brain nerve cells that die.”
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