研究人员发现脊髓性肌萎缩的新病因

Over 15 years ago, researchers linked a defect in a gene¹ called survival motor neuron -- or SMN -- with the fatal disease spinal² muscular atrophy³（肌肉萎缩） . Because SMN had a role in assembling the intracellular（细胞内的） machinery⁴ that processes genetic⁵ material, it was assumed that faulty processing was to blame. Now, University of North Carolina scientists have discovered that this commonly held assumption is wrong and that a separate role of the SMN gene -- still not completely elucidated⁶ -- is likely responsible for the disease's manifestations⁷. The research appears June 21, 2012 in the journal Cell Reports.

"There are a number of gene therapies and RNA therapies in the pipeline⁸ that may still work regardless of the underlying⁹ cause of the disease," said senior study author Gregory Matera, PhD, professor in the departments of biology and genetics and a member of the Program in Molecular¹⁰ Biology and Biotechnology in the UNC School of Medicine.

"But if those approaches don't pan out, it could be that the therapy isn't reaching the precise tissues where defective¹¹ SMN is most damaging," he added. "Our result is exciting because we now have a starting point to uncover what is truly causing this disease so we can more effectively treat it."

Spinal muscular atrophy is characterized by muscle weakness and wasting (atrophy) resulting from the progressive loss of motor neurons in the spinal cord. The disease is due to a partial loss of function in the SMN gene that normally loads up the "splicing¹²（拼接） " machinery with the proteins necessary for cutting and pasting the cell's genetic instructions together. Cells that completely lack SMN fail to correctly generate and process the genetic blueprint¹³ for the proteins needed to carry out the rest of the body's activities.

But in addition to roles in splicing, SMN has been implicated¹⁴ in a number of other processes that occur only in specific tissues, such as the formation of the junction¹⁵（连接） between muscle and nerve cells or the maintenance of muscle architecture. Thus Matera and his colleagues wondered if defective splicing was really responsible for spinal muscular atrophy or if one of these tissue-specific roles was the cause.

In this study, the researchers investigated whether they could disconnect SMN's "primary" role in splicing from the physical characteristics typical of spinal muscular atrophy. To do so, they first created fruit flies carrying the same genetic mutation¹⁶ that causes the disease. The mutant flies didn't survive to the larval stage and showed significant defects in locomotion¹⁷ as well as reductions in those important splicing proteins.

But when the researchers re-introduced functional¹⁸ SMN, only the larval（幼虫的） lethality¹⁹（杀伤力） and locomotor（移动的） defects -- not the level of splicing factors --were rescued. Therefore, this splicing function of SMN is not a major contributor to spinal muscular atrophy. Right now Matera and colleagues are using a number of highly sophisticated "-omics" methods such as proteomics（蛋白质组） and RNomics to pin down the real culprit.

The research was funded by the National Institutes of Health and the American Heart Association. Study co-authors from UNC were Kavita Praveen and Ying Wen.