Scientists have identified a protein that appears not only to be central to the process that causes Parkinson’s disease but could also play a role in muting the high from methamphetamine and other addictive drugs.
The action of the protein, known as organic cation transporter 3 or oct3, fills a longstanding gap in scientists’ understanding of the brain damage that causes symptoms like tremor, stiffness, slowness of movement and postural instability.
While these are found mainly in patients with Parkinson’s disease, there are more than three dozen other known causes of this array of symptoms, known as “parkinsonism.”
In a paper published online this week in the Proceedings of the National Academy of Sciences, scientists at the University of Rochester Medical Center and Columbia University have shown that oct3, a protein that shepherds molecules into and out of cells, plays a critical role, bringing toxic chemicals to the doorstep of the brain cells that die in patients with Parkinson’s disease.
The team found that oct3 is involved in the brain’s response to addictive drugs like methamphetamine as well.
Precisely what causes Parkinson’s disease remains largely a mystery. Some cases have a known genetic basis, and most others are attributed to environmental causes or a combination of gene-environment interactions.
Doctors know that symptoms of Parkinson’s stem from the death of a very small, specialized group of brain cells known as dopamine neurons, which produce a chemical needed by another area of the brain to help us move freely. It’s not until most of those brain cells have already died that patients begin to show symptoms.
For decades, scientists have been trying to understand why those cells die.
The latest paper supports a role for astrocytes, a type of cell that is the most common in the brain but which has been often overlooked by scientists focused more on cells known as neurons that send electrical signals.
Astrocytes’ role in Parkinson’s is no surprise to brain experts who have also identified them as a player in Alzheimer’s disease, amyotrophic lateral sclerosis, epilepsy, and other diseases.
“Astrocytes are definitely much more than support cells in the brain,” said Kim Tieu, Ph.D., a corresponding author of the paper and assistant professor in the Department of Environmental Medicine at the University of Rochester Medical Center.
“Scientists are discovering their involvement in many diseases. The latest results point to their role in Parkinson’s disease.”
The team also analyzed brain tissue from people who died of Parkinson’s disease and found that oct3 is active in astrocytes in the brain region affected by Parkinson’s disease. They found the same thing in mice, where the absence of oct3 correlated exactly to areas of the brain where neurons were not damaged.
The team also showed that oct3 plays a role in the brain’s response to methamphetamine. Oct3 is critical for helping astrocytes soak up excess dopamine in the space around neurons. When dopamine isn’t removed as quickly or thoroughly as usual, people can feel euphoric, but they can also experience brain damage. The finding that oct3 may play a role matches other scientists’ observations that people in whom oct3 activity is reduced have a higher potential for addiction.
The molecule might also offer a new target for treating depression. Many antidepressants work by allowing the brain chemical serotonin to stay available in the brain longer than it otherwise would. Since one of oct3’s functions is to remove serotonin from the brain, blocking it may offer a new avenue to treat depression.
The chemicals that the team used to block oct3 in mice would be toxic in people, and there is no drug available for people now that blocks or boosts oct3, Tieu and Przedborski said. But such a drug might be useful for Parkinson’s, drug addiction, and depression.
“How you choose to manipulate the function of oct3 depends on the source of the toxic molecules,” said Tieu, who is also a scientist in the University’s Center for Neural Development and Disease.
“You would try to lessen its effects in a condition where it makes a toxic molecule available to vulnerable cells, as illustrated in the current model of Parkinson’s disease. But in the case of drug addiction, you might try to increase it, to lessen the impact of a drug like methamphetamine.”
Source: University of Rochester