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Leading ALS Researcher to Lead Scientific Effort at Pitt Brain Institute’s Live Like Lou Center

PITTSBURGH, Sept. 11, 2015 – Clearing a blocked passageway between the nucleus and the rest of the cell could present a new opportunity for treating some cases of amyotrophic lateral sclerosis, or ALS, according to a neurobiologist who co-led the study, published recently in Nature, and who has  joined the University of Pittsburgh Brain Institute to continue his scientific efforts at the Live Like Lou Center for ALS Research.
Christopher Donnelly, Ph.D., assistant professor of neurobiology at Pitt School of Medicine, will conduct ongoing research into this pathway and other possible treatment approaches at the Live Like Lou Center, established earlier this year and named for a patient advocacy organization started by Neil and Suzanne Alexander. Mr. Alexander died of ALS in March.
“Pitt is home to renowned scientists and medical practitioners, one of the largest brain tissue research repositories in the world and, most importantly, a strong community that is determined to make a difference in the fight against ALS,” Dr. Donnelly said. “I am delighted to pursue this work at an institution that has made a profound commitment to treating and hopefully curing this devastating disease.”
“We are thrilled to have Dr. Donnelly bring his accomplishments and creativity to the Brain Institute,” said Peter Strick, Ph.D., Pitt’s Dr. Thomas Detre Professor and Chair of Neurobiology and scientific director of the Brain Institute. “His research is taking our understanding of ALS therapeutics in new and promising directions.”
In ALS, the motor neurons responsible for movement die, leading to progressive muscle weakness and eventual death due to breathing problems and other complications. According to Dr. Donnelly, ALS, like cancer, probably has many different causes, making it difficult to find one-size-fits-all solutions.
“One out of 10 ALS cases is familial and in 40 percent of those we have observed an abnormal repeating gene sequence,” he said of the work he conducted while at Johns Hopkins University. “We wanted to see what proteins that sequence made, so we took skin cells from patients that carried the mutations, converted them into induced pluripotent stem cells and then generated motor neurons for some experiments.”
When proteins are made from DNA blueprints, RNA molecules act as a template. The repeating gene sequence produced RNA that behaved like a sticky spider web and bound other proteins to it, the Hopkins team found. In particular, the sticky RNA clog up what’s known as the nuclear pore complex, a tunnel-like structure that tightly controls the traffic of molecules in and out of the cell’s nucleus.
“One of the hallmarks of ALS is an overabundance of proteins in the cell’s cytoplasm,” Dr. Donnelly said. “It’s like a car accident in the tunnel is preventing proteins from making their way through to the other side. Eventually, the damaged cells stop functioning and die.”
Such neurodegeneration was suppressed among Drosophila flies with the gene version of ALS that were given an agent that inhibited the sticky RNA. Another molecule they tested, which acts by altering proteins that control traffic through the nuclear pore complex, also slowed neurodegeneration, the researchers said.
“This pathway could offer us a new way of treating ALS,” Dr. Donnelly said. “While there might be different initial triggers of the disease, we suspect many of them might influence the function of this tunnel. We want to further explore this possibility.”
Dr. Donnelly received his doctorate from the University of Delaware and did his postdoctoral training at Johns Hopkins.

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