3/29/2018 3:50:03 PM
An international team of researchers that includes Illinois Computer Science PhD candidate Faraz Faghri and Professor Roy H. Campbell has proven that mutations in the neuronal transport gene KIF5A are associated with amyotrophic lateral sclerosis, or ALS.
The findings identify how mutations in KIF5A disrupt the transport of key proteins up and down long, threadlike axons that connect nerve cells between the brain and the spine, eventually leading to the neuromuscular symptoms of ALS.Also known as Lou Gehrig's disease, ALS is progressive and fatal, often beginning with muscle twitching, weakness in a limb, or slurred speech. The disease eventually affects control of the muscles needed to move, speak, eat, and breathe.
The discovery, published in the March 21, 2018, issue of Neuron, was led by Bryan Traynor of the Intramural Research Program of the National Institute on Aging at the National Institutes of Health, and by John Landers of the University of Massachusetts Medical School. Key funding support came from the NIA, the National Institute of Neurological Disorders and Stroke (NINDS) at NIH, and several public and private sector organizations.
The research effort required analyzing a massive amount of genetic data.
The NIH team performed a large-scale, genome-wide association study, while the University of Massachusetts team concentrated on analyzing rare variants in next-generation sequence data. More than 125,000 samples were used in this study, making it by far the largest such study of ALS performed to date.
“The extraordinary teamwork that went into this study underlines the value of global, collaborative science as we seek to better understand devastating diseases like ALS,” said Dr. Richard J. Hodes, director of NIA. “These types of collaborative data collection and analysis are important in identifying the pathways underlying disease and in developing approaches to treatment and prevention.”
Faghri, who works with Campbell and is a consultant to the NIH, said the massive amount of data being analyzed required new approaches.
“We developed new methods and computational environments for analyzing these large datasets,” Faghri said. “Achievement of the potential genetic and healthcare breakthroughs clearly requires new algorithms, computational systems, and disruptive data-analysis methods.”Campbell added that he was excited that computer science played such a key role.
“This type of success encourages computer scientists to collaborate with the medical community to take advantage of the emerging big data and machine learning breakthroughs to offer new discoveries and enhance healthcare delivery,” he said.
KIF5A regulates proteins that serve as tiny intracellular motors. Problems with these proteins are connected to ALS, Parkinson’s disease and Alzheimer’s disease, and were previously connected to some less-common neurodegenerative diseases with muscle weakening, stiffening and spasticity symptoms similar to ALS.
“Axons extend from the brain to the bottom of the spine, forming some of the longest single cellular pathways in the body,” Traynor said. “KIF5A helps to move key proteins and organelles – specialized parts of cells -- up and down that axonal transport system, controlling the engines for the nervous system’s long-range cargo trucks. This mutation disrupts that system, causing the symptoms we see with ALS.”
Traynor cautioned that the discovery still leaves much more work to be done.
“While this is unlikely to be a very common genetic cause for ALS, it identifies important new directions to explore possible future gene therapies,” he said.
The paper: https://doi.org/10.1016/j.neuron.2018.02.027