SMA Research: Saving Shortened SMN Protein

Preserving a shortened version of the SMN protein rescued SMN-deficient cells, opening the door to a possible new therapeutic strategy

Approximately 80-90 percent of SMN protein produced from the SMN2 gene includes a cellular "trash me" tag that marks it for destruction by a cellular waste-disposal system. In cell culture experiments, researchers have shown that modifying this tag can "rescue" the protein, allowing it to linger longer. The findings suggest a new way to develop therapies to treat spinal muscular atrophy (SMA).
Article Highlights:
  • Deficiency of a protein called SMN for "survival of motor neurons" is the underlying molecular cause of spinal muscular atrophy (SMA).
  • The human SMN1 and SMN2 genes that carry codes for the SMN protein are nearly identical, but instructions from SMN1 lead to production of functional SMN protein, while those encoded in SMN2 result in a shortened and highly unstable version of the protein approximately 80-90 percent of the time.
  • A team of investigators has shown that the shorter SMN protein produced from SMN2 is still functional, but that its rapid decay, stemming from a molecular "degradation" signal, prevents it from imparting any appreciable benefit. 
  • The findings suggest it may be possible to interfere with this "trash me" tag, a strategy that may increase the stability of SMN2-derived protein and lessen the severity of the disease. 


by Amy Madsen on March 17, 2010 - 4:26pm

A research team at the University of Pennsylvania in Philadelphia has characterized the mechanism responsible for rapid decay of the survival of motor neurons (SMN) protein that is encoded by the human SMN2 gene and which plays a key role in a variety of therapeutic strategies under development for spinal muscular atrophy (SMA)

In addition, the researchers showed that SMN2-derived protein, when stabilized, appears able to serve its critical function of providing support to cells that otherwise would die. Until now, it hasn't been clear whether the shorter SMN protein molecules were nonfunctional because of their instability or because of other factors.

The protein's instability, a feature the team showed is built into its very design, is responsible for rendering it unable to prevent the loss of nerve cells that is seen in people with SMA. 

The investigators are moving ahead with drug screening efforts aimed at uncovering compounds able to prevent the rapid decay of this otherwise helpful SMN protein. 

About the molecular basis of SMA 

SMA is caused by deficiency in levels of the SMN protein, which normally supports and protects nerve cells called motor neurons. 

Both the SMN1 and SMN2 genes on chromosome 5 carry instructions for production of the SMN protein. While instructions encoded in the SMN1 gene lead to full-length, functional SMN protein, only 10-20 percent of SMN2-derived protein is full-length. The other 80-90 percent, it now appears, can be functional if it lasts long enough in cells. 

Missing or mutated SMN1 genes result in SMA. The small amount of full-length SMN protein made from the SMN2 gene can compensate somewhat for the loss of the SMN1 gene, and, generally, the more SMN2-derived protein a person has, the less severe the disease course will be. (See In Focus: Spinal Muscular Atrophy.) 

About the new findings 

In the new findings, published in the March 2010 issue of Genes & Development, Gideon Dreyfuss and Sungchan Cho at the University of Pennsylvania describe how the short, SMN2-derived protein molecules apparently contain a degradation signal, known as a "degron." This biochemical "trash me" tag alerts the cell's waste disposal system, normally responsible for degrading malformed or nonfunctional proteins, to quickly destroy the SMN2-derived SMN protein. Unfortunately, the disposal system is too efficient in this case. If it weren't for its activity, the SMN2-derived protein would last longer and perform its normal function, the researchers found. 

The protein produced from SMN2 instructions "is not a useless SMN," said Gideon Dreyfuss, a Howard Hughes Medical Institute investigator at Penn. "It has the same, or at least some, of the activity that normal SMN has. It can rescue cells depleted of SMN."  

When Dreyfuss and Cho manipulated SMN2 genetic instructions to force the addition of five amino acids (protein building blocks) to the end of the protein containing the degron, the resulting protein proved to be stable, surviving almost double the length of time experienced by its chemical cousin saddled with the "trash me" tag. 

The findings suggest it may be possible to interfere with the protein degradation tag, increasing the longevity of SMN2-derived protein and ultimately leading to decreased severity of the disease. 

About strategies for SMA therapeutics

Although MDA did not directly support this project, it funds a number of researchers who are working on various strategies aimed at advancing SMA therapeutics to clinical trials. Potential avenues include: 

  • replacing a missing or defective SMN1 gene with a working copy that will produce SMN protein (See Gene Therapy Rescues Mice with SMA);
  • coaxing production of more full-length SMN protein from SMN2 gene instructions (See Progress in SMA Research);
  • manipulating the shortened protein produced from SMN2 instructions, for example by forcing it to include exon 7 (See Masking Unwanted Instructions); and
  • increasing the stability of the SMN2-derived protein, as in the new findings.

Meaning for people with SMA 

The findings shed light on the molecular underpinnings of SMA and open up an additional avenue, among several currently under investigation, in the pursuit of therapeutic strategies for the disease.  

The Dreyfuss lab and pharmaceutical giant Merck currently are collaborating on a large-scale effort to screen drug compounds that may stabilize the shortened SMN2-derived SMN protein and allow it to provide critical support to motor neurons. 

We're trying "to find compounds that increase SMN protein in SMA patients' cells," Dreyfuss said. "The effort is ongoing, and we are quite encouraged by what has emerged from this so far." 

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