ADVERTISEMENT

Tiny RNA Snippet May Play a Role in Parkinson's

Genetic "dimmer switches could possibly become a new target in the fight against the neurodegenerative disorder
midbrain picture



© SCIENCE
"Dimmer switches" that control the level of protein created from a given gene may regulate the development, function and, ultimately, the life span of cells that begin to vanish from the brain at the onset of Parkinson's disease.

The finding, published in last week's Science, could offer a new therapeutic target for treating the neurodegenerative disorder—making it one of the first to tie these protein modulators, small snippets of RNA known as microRNAs, to human disease.

Parkinson's, which affects an estimated 500,000 Americans, is a debilitating illness of unknown origin characterized by tremors, stiff movements and the deterioration of motor ability. It is believed to be jump-started by a loss of neurons in a midbrain region called the substantia nigra. These cells, more of which are killed in the course of the disease, produce the chemical neurotransmitter dopamine (which is linked to movement control) in order to communicate with one another and cells in different brain areas.

As cells go about their day-to-day business, they transcribe the genes in their DNA into messenger RNA (mRNA), which is then turned into proteins that perform most of those cells' functions. Some proteins serve as transcription factors that determine which genes are active or dormant at a particular time. "They are basically light switches for genes," says Asa Abeliovich, an assistant professor of neuropathology at Columbia University Medical Center and study co-author. On the other hand, microRNAs, which regulate the mRNAs slated to become protein, "are like the dimmer switches."

MicroRNA strands are short segments of RNA that is coded by the genome. They are clipped from longer microRNA precursors by two enzymes. In one experiment, Abeliovich's team created mutant mice that lacked the ability to make one of these two enzymes in their midbrain. Sure enough, Abeliovich says, the symptoms displayed by "the mice were reminiscent of [Parkinson's] disease," complete with loss of dopamine neurons. Among the mice¿s problems: they rarely left the corners of the large cages where they were placed.

Next, the researchers examined postmortem brains of Parkinson's patients to determine which type of microRNA was noticeably deficient in the midbrain regions. They zeroed in on a type called miR-133b. Further examination showed that while miR-133b regulates dopamine neurons, its absence does not destroy them (although its absence does disrupt their function). It's clearly not the only microRNA whose absence relates to Parkinson¿s,¿ explains Abeliovich. "We still need to figure out which other ones are involved."

For now, the scientists have determined that miR-133b likely works in a negative feedback loop with a transcription factor called Pitx3: during the course of its work, Pitx3 transcribes miR-133b from the DNA in the neurons. Pitx3 is then stopped from transcribing further by miR-133b. Abeliovich believes this control route is crucial to the function of these cells, which he says are extremely responsive to environmental stimuli. "Dopamine neurons are very sensitive to inputs and they're highly regulated in their function," he notes. "You need to have a very responsive sort of system."

In an editorial accompanying the Science article, Sébastien Hébertch and Bart De Strooperch, researchers in molecular and developmental genetics at the Catholic University of Leuven in Belgium, express excitement over the new discovery. "Clinical studies will rapidly determine the extent to which versions of microRNA contribute to the pathogenesis of sporadic [noninherited] Parkinson's," they write. "However, the role of microRNA as a potential therapeutic target remains a challenging question."

For his part, Abeliovich suggests that tweaking microRNA behavior—inhibiting its creation or possibly making more of it—may have a positive effect on Parkinson's sufferers. But he stresses that this goal is still far off. "It's hard to know if we'd want to tweak microRNAs up or down," he says. "We don't have drugs for these things and we don't know which ones we'd want to target."

Rights & Permissions
Share this Article:

Comments

You must sign in or register as a ScientificAmerican.com member to submit a comment.
Scientific American Dinosaurs

Get Total Access to our Digital Anthology

1,200 Articles

Order Now - Just $39! >

X

Email this Article

X