Specialized RNA molecules could counter ALS neurodegeneration
Researchers at Penn Medicine have discovered short RNA chaperones that bind to the primary target of ALS, restore its function, and protect motor neurons in a preclinical model, pointing toward a new RNA-based therapeutic strategy.
2 min. read
Misshapen proteins cause a mess of trouble—particularly in neurodegenerative diseases. But a new study from Penn Medicine suggests it’s possible that giving them a little bit of extra support could keep them working correctly, and even reverse the damage they have caused.
(Left) James Shorter, biochemistry and biophysics professor at the Perelman School of Medicine, and Katie Copley, a former graduate student in the Shorter Lab.
(Image: Courtesy of Penn Medicine)
The new research focuses on one such aberrant protein, TDP-43, which binds to RNA in the cell’s nucleus and is responsible for regulating thousands of human genes. If TDP-43 turns from a healthy, liquid-like phase into diseased, fibrous solid-like aggregates, its presence can be fatal. This protein is one of the key drivers of the diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—a discovery first made by pioneering Penn Medicine scientists Virginia M.-Y. Lee and the late John Trojanowski.
There are currently no cures for ALS or FTD, but that could change. In a new study published in Science, researchers at the Perelman School of Medicine have reported short RNA molecules that could reverse TDP-43 aggregation and restore its function, an important advance toward RNA-based treatments for ALS and FTD.
“In these diseases, you're really fighting against two things: this nuclear loss of TDP-43 function—disrupting RNA splicing and processing—and a cytoplasmic gain of toxic function through protein aggregation,” says James Shorter, a professor of biochemistry and biophysics at the Perelman School of Medicine and a senior author of the study. For nearly two decades, concurrent with and following on Lee and Trojanowski’s discoveries, Shorter has studied the causes and mechanisms of TDP-43’s misfolding and sought methods to prevent and reverse it.
When TDP-43 misfolds and collects in the cytoplasm, it no longer performs its normal function regulating the RNA in the nucleus and forms toxic aggregates. But Shorter and his colleagues have found that short RNA chaperones could reverse TDP-43 aggregation and restore its function.
The researchers have found that in binding to TDP-43, the Clip34 RNA stabilizes the site where the protein usually engages with RNAs—the RRMs—while destabilizing another area called the prion-like domain. This secondary area is known to drive protein misfolding that causes neurodegeneration.
“We think that the way the short RNA binding affects the structure of that prion-like domain is important for keeping TDP-43 soluble,” says Katie Copley, a former graduate student in the Shorter Lab and the lead author of the study.
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