SMA Disease Course May Be Affected by ZPR1

Zinc finger protein 1 (ZPR1) appears to be a 'protective modifier' of spinal muscular atrophy, making it a potential target in the development of therapies

Adequate levels of zinc finger protein 1 (ZPR1) appear to be a "protective" modifier of spinal muscular atrophy (SMA), an MDA-supported team of scientists has reported.

Modifiers influence disease onset and severity by changing various biological pathways.

The identification of ZPR1 as a modifier reveals a potential target for therapy development and also sheds light on the mechanisms that drive SMA.

SMN2 copy number usually predicts disease course

SMA is caused by mutations in the SMN1 gene that result in a deficiency of functional SMN protein. In humans, a nearly identical gene called SMN2 produces some partially functional SMN protein. Typically, the more copies of the SMN2 gene a person with SMA has, the less severe the symptoms of the disease.

But sometimes the SMN2 copy number doesn't predict a person's disease course. This has been observed in people with SMA as well as in mouse models of the disease.

One explanation is modifiers — genes, proteins or other biological components that can influence disease course.

Reduced ZPR1 activity correlates with more severe SMA

The new findings showed that ZPR1 protein levels appear to be inversely correlated with SMA disease severity; the higher the levels of ZPR1, the milder the disease.

Study results showed that in mice with an SMA-like disease, changes in the activity of either the ZPR1 or SMN protein alter levels of both proteins, indicating likely genetic interaction between the two.

The researchers found that reduced ZPR1 activity caused increased degeneration and loss of spinal motor neurons (nerve cells that control muscle activity), increased respiratory problems, a more severe disease process, and reduced life span in mice with an SMA-like disease.

Additionally, they noted, the ZPR1 protein plays a key role in:

• helping the SMN protein localize to its correct place in the cell;

• stimulating the growth of parts of motor neurons called neurites, which project from the cell body; and

• rescuing growth defects in the axons of SMN-deficient spinal cord neurons. (Axons are the long fibers that carry signals away from motor neuron cell bodies.)

Abnormally low levels of ZPR1 affect the protein's ability to carry out these necessary functions.

Laxman Gangwani, associate professor at the Center of Excellence in Neurosciences, Texas Tech University Health Sciences Center in El Paso, Texas, and colleagues reported the findings online March 14, 2012, in Human Molecular Genetics. MDA supported Gangwani for his contribution to this work.

ZPR1 may be a therapeutic target

If the new findings are corroborated, ZPR1 potentially could serve as a target for SMA therapy development.

Genetic testing to determine ZPR1 protein levels could help inform physicians and families about the likely disease course in affected individuals.

Additional study of the ways in which ZPR1 functions as a modifier may shed light on the mechanisms that drive SMA.