New Insights Into Spinal Muscular Atrophy

Main Category: Muscular Dystrophy / ALS
Also Included In: Pediatrics / Children's Health;  Genetics;  Neurology / Neuroscience
Article Date: 31 May 2008 - 1:00 PDT

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Researchers from the University of Pennsylvania School of Medicine discovered that the effect of a protein deficiency, which is the basis of the neuromuscular disease spinal muscular atrophy (SMA), is not restricted to motor nerve cells, suggesting that SMA is a more general disorder. This new insight will allow for better understanding of how this complex disease arises. Gideon Dreyfuss, PhD, the Isaac Norris Professor of Biochemistry and Biophysics and Investigator, Howard Hughes Medical Institute and colleagues, report their findings in Cell.

SMA is a group of hereditary diseases that causes weakness and wasting of the voluntary muscles in the arms and legs of infants and children. The disorders are a result of genetic lesions in a gene called survival of motor proteins (SMN) that cause a deficiency in the SMN protein. This protein is essential for all cells, but reduced levels of SMN cause spinal muscular atrophy. Why this seemingly cell-specific reduction happens is not known.

SMN normally works in all cells to bring small RNAs together with specific proteins to form particles called snRNPs (pronounced snurps). snRNPs are the molecular machines that splice different parts of RNA together to form the messenger RNA (mRNA) before it leaves the nucleus to travel to the cytoplasm. Here, mRNAs get translated into working proteins.

"SMN plays a key role in determining the inventory of the different types of snRNPs in all cells, what we call the snRNP repertoire or the 'snRNPertoire,'" says Dreyfuss. "When SMN levels are reduced, the biochemical balance needed to make the snRNP complexes for splicing RNA is impaired."

The Dreyfuss lab looked at reduced SMN levels in cultured cells and mice and found that changes in levels of the snRNPs, as well as the mRNAs - their spliced products - were affected, producing numerous abnormal mRNAs. These effects varied from tissue to tissue. The findings suggest that spinal muscular atrophy is a general disease of splicing.

"Now we know that SMA is clearly a disease that not only affects motor neurons, but all cell types when the gene for SMN is damaged," says Dreyfuss. In the end, concludes Dreyfuss, this is a different way to look at the disease. Finding a way to restore SMN levels in the entire body is one therapeutic approach to aim for, based on these findings.

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Penn co-authors are Zhenxi Zhang, Francesco Lotti, Kimberley Dittmar, Ihab Younis, Lili Wan, and Mumtaz Kasim. The study was funded by the Association Francaise contre les Myopathies and the Howard Hughes Medical Institute.

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals - its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center - a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Source: Karen Kreeger
University of Pennsylvania School of Medicine

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