ZPR1 Protein May Be New Potential Therapeutic Target for SMA, Preclinical Study Suggests

Increasing the amount of ZPR1 — a protein found in low levels in people with spinal muscular atrophy (SMA) — improved motor function and extended the lifespan of a mouse model of SMA, a study reports.

The data, which also identified the protein as a direct regulator of the production of survival motor neuron (SMN), the protein lacking in SMA, suggests that ZPR1 may be a new potential therapeutic target for this neurodegenerative disorder.

The study, “ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy,” was published in the journal Brain.

SMA is caused by mutations in the SMN1 gene leading to little or no SMN protein production, a protein essential for muscle health. The existence of a second survival motor neuron gene (SMN2), with an identical sequence, can partially compensate for the loss of SMN1-produced SMN, but much of the protein regularly produced by the SMN2 gene is shorter and therefore nonfunctional.

SMN2 has been pinpointed as a therapeutic target to help produce higher levels of SMN by increasing its activation. For example, Spinraza (nusinersen) — the first approved SMA therapy — works by acting on the SMN2 gene and promoting the production of a full-length, functional SMN protein.

However, the molecular mechanisms that regulate the activation of SMN genes remain largely unknown.

Previous studies have shown that ZPR1, a protein whose function is still unclear, is lower in SMA patients and that mice deficient in this protein develop SMA-like symptoms, with an association between ZPR1 levels and disease severity.

While these data point to a potential therapeutic benefit in increasing ZPR1 levels, no studies have tested this hypothesis in animal models of SMA.

To address this, researchers in Texas evaluated the therapeutic effects of increasing ZPR1 levels in SMA by genetically modifying an SMA mouse model to overproduce the protein.

Compared with SMA mice that did not overexpress ZPR1, the animals with an overproduction of the protein showed significantly increased overall growth, decreased neurodegeneration and muscle atrophy, improved motor function and muscle strength, and an extended lifespan.

In addition, while SMA mice had up to 45% lower levels of ZPR1 in several tissues, SMA mice with higher ZPR1 levels showed a significant three-fold increase in both ZPR1 and SMN levels in the spinal cord and brain, as well as in the heart and lungs.

In agreement, induced overproduction of the protein in cells from SMA patients grown in the lab resulted in a four-to-five-fold increase in both ZPR1 and SMN levels.

These data suggest a close association between ZPR1 levels and SMN production. “ZPR1 [overproduction] in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice,” the researchers wrote.

Further analyses revealed that this ZPR1-dependent boost in SMN production lessened SMA-associated accumulation of DNA damage (leading to nerve cell loss) in both SMA mice and patient cells.

Using these SMA models, the researchers also found that ZPR1 directly regulates the production of SMN by binding to RNA polymerase II — a major enzyme responsible for the first steps of translating information from genes to proteins — and interacting with both SMN1 and SMN2 genes.

“These findings suggest that modulation of ZPR1 levels directly correlates and influences levels of SMN genes [activation] and ZPR1 is a [positive] regulator of the SMN1 and SMN2 genes,” the researchers wrote.

According to the team, the protein is a promising therapeutic target for developing a new approach for treating SMA, but it might be more useful and effective when used in combination with other SMA therapies.

Further studies are required to better understand ZPR1’s mechanisms of action and to test various methods of increasing ZPR1 levels in preclinical studies before moving to human clinical trials.