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MicroRNA Triggers Protective Response in Mice with ALS


For release: Tuesday, March 2, 2010

The neuromuscular junction of a healthy mouse looks similar to a bunch of grapes, and is shown in red and green thanks to the use of fluorescent antibodies.

In a recent study, investigators found that mice with amyotrophic lateral sclerosis (ALS) mount a protective, though ultimately unsuccessful, response against the disease. Central to this response is a small molecule called microRNA-206.   Identifying ways to stimulate the molecule or its effects may lead to new treatments for ALS.

ALS involves the degeneration of muscle-controlling nerve cells known as motor neurons.  The loss of these cells leads to muscle weakness and wasting and eventual respiratory failure.  For patients, the disease is typically fatal within five years of diagnosis.  There is only one approved drug treatment, and it prolongs survival by just a few months.

The new study was a collaboration between Joshua Sanes, Ph.D., a professor of molecular and cellular biology at Harvard University, and Eric Olson, Ph.D., a professor of molecular biology at the University of Texas Southwestern (UT Southwestern) Medical Center in Dallas.  Dr. Sanes is an expert on the development of nerve-muscle connections, and Dr. Olson is an expert on the biology of cardiac muscle.

The study was published in Science*, and was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS).  Co-lead authors of the study were Andrew H. Williams, a graduate student at UT Southwestern, and Gregorio Valdez, Ph.D., a postdoctoral fellow at Harvard.

In previous work, Dr. Olson showed that microRNAs (small bits of the chemical RNA) affect the way cardiac muscle responds to heart attacks and other injuries; some microRNAs appear to add to the damage, while others appear to counteract it. 

The researchers hypothesized that mircoRNAs in skeletal muscle might affect the nerve and muscle damage that occurs in ALS.  They scanned the activity of hundreds of microRNAs in mice with a mutation in the SOD1 gene, which is linked to familial ALS in people.  They found one – microRNA‑206 – that is increased in fast-twitch muscles at the onset of the disease and apparently slows its course.  When the researchers genetically deleted microRNA-206 from the mice, the disease progressed more rapidly.

Further experiments revealed how microRNA-206 reins in the course of ALS.  As a motor neuron degenerates in ALS, it loses its connection to muscle, called the neuromuscular junction.  The researchers discovered that microRNA-206 activates a pathway that helps repair these junctions – but the disease apparently destroys them at a faster rate than microRNA-206 can fix them.  In one set of experiments, the investigators found that in mice with acute nerve injuries (not ALS), the repair of neuromuscular junctions occurred more slowly if the mice lacked microRNA-206.

The researchers traced multiple steps in the repair pathway.  They discovered that microRNA-206 indirectly increases the level of a protein called FGFBP1, which helps establish mature neuromuscular junctions.

These new findings dovetail with recent, independent research on the genetics of ALS.  Several studies show that two genes involved in RNA metabolism, called TARDBP and FUS, are at the root of rare, inherited forms of ALS.

The researchers wrote in Science that their results “suggest opportunities for intervention through the modulation of microRNA-206 or the downstream pathways that it regulates.”

Drs. Williams and Olson have filed a patent application related to the work.

- By Daniel Stimson, Ph.D.

Willams AH et al.  “MicroRNA-206 Delays ALS Progression and Promotes Regeneration of Neuromuscular Synapses in Mice.”  Science, December 11, 2009, Vol. 326, pp. 1549-1554.

 The neuromuscular junction of a healthy mouse looks similar to a bunch of grapes, and is shown here in red and green thanks to the use of fluorescent antibodies.
A neuromuscular junction of a healthy mouse, visualized using fluorescent antibodies against proteins that are enriched in nerve endings and adjoining muscle. Courtesy of Dr. Joshua Sanes.

Last Modified February 9, 2011