Molecular Basis Of Leading Genetic Cause Of Infant Death Discovered

"Our work describes the function of the SMN protein and links it to spinal muscle atrophy, opening up the possibility to search for therapeutics," reports Gideon Dreyfuss, Ph.D., the Isaac Norris professor of biochemistry and biophysics and a Howard Hughes Medical Institute investigator. Reduced levels or mutations in the SMN protein lead to spinal muscle atrophy. Dreyfuss and his colleagues -- Penn researchers Livio Pellizzoni, Bernard Charroux, and Naoyuki Kataoka -- discovered that SMN has a novel function that is essential for all cells to produce mRNA. Motor neurons appear to be particularly sensitive to defects in SMN, so much so that a deficiency in SMN leads to the death of these cells and results in the atrophy of the muscles they control.

The group's findings will be published in tomorrow's issue of Cell. A full-page photo of a human cell whose nuclear structures have been drastically affected by a mutant SMN protein is featured on the cover of the journal.

"This paper is an important step towards an effective treatment for spinal muscle atrophy," states Kenneth H. Fischbeck, MD, chief of the Neurogenetics Branch at the National Institute of Neurological Disease and Stroke and a former Penn neurologist. "Now scientists will be able to work back from the biochemistry of the disease to eventually design new therapies."

The findings demonstrate that the SMN protein plays a crucial role in the genesis of mRNA from a precursor called pre-mRNA. The conversion of pre-mRNA to mRNA takes place in the cell nucleus in a process called splicing. It is a critical step in the pathway of gene expression, and ultimately, in the production of a functional protein.

This genetic splicing is analogous to splicing a film together--getting the right sequence, cutting out the unnecessary parts, and putting it back together in the right order. "Obviously, this splicing process needs to operate efficiently and with high fidelity," explains Dreyfuss. "A complex molecular machine assembles on each pre-mRNA to carry out the splicing process. This is a modular splicing machine that is re-used repeatedly, cycle after cycle. It is comprised of many proteins and of small specialized particles called snRNPs. Our research shows that SMN and its entourage of helper proteins are required for the proper form and function of snRNPs and for maintaining the splicing machine in an active form so that it can be used for multiple rounds of splicing."

In cells of patients with spinal muscle atrophy, the splicing process is drastically compromised. Human motor neurons contain some of the highest concentrations of snRNPs, as well as SMN, of any cells in the body. When there is a deficiency of SMN, the motor neurons appear to be the first cells to suffer, and cell death eventually results.

As part of this work, the team has re-created the biochemical activity of SMN in a test tube. "This should make it possible to directly search for compounds that may enhance or substitute for SMN's activity, and thus serve as potential drugs for treating spinal muscle atrophy," adds Dreyfuss.