Misshapen proteins cause a mess of trouble-particularly in neurodegenerative diseases. But a new study 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.
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, PhD, MBA and the late John Trojanowski, MD, PhD.
There are currently no cures for ALS or FTD, but that could change. In a new study published today in Science, researchers at the Perelman School of Medicine at the University of Pennsylvania 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," said James Shorter, PhD, a professor of Biochemistry and Biophysics at the Perelman School of Medicine at Penn 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.
