By reverse engineering human skin cells to become induced pluripotent stem cells (iPSCs) and then coaxing them to become neural dopamine cells, scientists in the US have developed a way to study a genetic cause of Parkinson’s disease in lab-made neurons. Their findings, which they write about in the 7 February issue of Nature Communications, reveal some potential new drug targets for Parkinson’s and a new platform to screen treatments that might mimic the protective functions of parkin, the gene they investigated.
Parkinson’s disease is a progressive neurological disorder that results from the death of dopamine-secreting neurons in a region of the brain that controls movement. In the US there are 500,000 people with Parkinson’s disease, and 50,000 new cases every year. There is no cure.
Most cases have no specific cause, but around 1 in 10 can be attributed to known genetic factors. One of these is mutations in the parkin gene.
To study the effect of the parkin gene in brain cells, you have to study live human neurons. But they are hard to study because they live in complex networks in the brain, ruling out the possibility of extracting them.
And you can’t use animals, because when they lack the parkin gene, they don’t develop Parkinson’s disease: human neurons are thought to have “unique vulnerabilities” in this respect.
(The suggestion is that the larger human brain uses more dopamine to support the neural computation that is needed to enable us to walk on two legs, compared to the four-legged movement of almost all other animals.)
But in 2007, scientists in Japan described how they made human stem cells (iPSCs) without using embryos, and since then, lead author of the Nature Communications study, Dr Jian Feng from the University at Buffalo (UB) in New York, and colleagues, have been looking for a way to use the technology to study neurons with mutations in the parkin gene.
Feng, a professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences, said in a press statement that the advent of iPSCs was a “game-changer” for their field of work:
“Before this, we didn’t even think about being able to study the disease in human neurons.”
“The brain is so fully integrated. It’s impossible to obtain live human neurons to study,” he added.
For their study, Feng and colleagues reverse engineered human skin cells to make iPSCs. The skin cells came from four people: two with a rare type of Parkinson’s disease where parkin causes the disease, and two healthy people 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,” said Feng.
Feng and colleagues also found that mutations in parkin stop it being able to tightly control 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,” said Feng.
But they found that when it is mutated, parkin loses the ability to regulate MAO, so the level goes up.
“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,” explained Feng, who noted that one of the drugs currently used to treat Parkinson’s disease slows the activity of MAO and in trials has been shown to slow disease progression.
Fend said they discovered that a key reason for the death of dopamine neurons was oxidative stress due to there being too much MAO around. But before the neurons die, the precise action of dopamine in helping the neural computations that support movement, is disrupted by mutations in parkin.
“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,” said Feng.
When the researchers delivered normal parkin into the neurons with the mutations, the defects were reversed. This is what makes them think such neurons could be used as a platform for screening new drug candidates that could mimic the protective effect of normal parkin.
The University of Buffalo has applied for patent protection on the screening platform.
Although parkin mutations are responsible for a small proportion of Parkinson’s cases, the researchers believe that understanding how the gene works could be relevant to all cases of the disease.
Written by Catharine Paddock PhD