Compound found in grapes, peanuts may be SMA treatment candidate

Activating a molecular recycling process called autophagy can improve motor function and extend lifespan in a nematode worm model of spinal muscular atrophy (SMA), a new study reports.

“We provide the first evidence that pharmacological activation of autophagy enhanced neuromuscular performance in the severe C. elegans SMA model,” researchers wrote.

The scientists speculated that autophagy-activating drugs might be useful as add-on therapies for treatments targeting the underlying cause of SMA. Based on their data, researchers identified a specific autophagy enhancer called resveratrol as the most promising candidate for further studies. Resveratrol is a naturally occurring compound found in several types of fruits, such as grapes, blueberries, raspberries, and peanuts.

The study, “Pharmacological Activation of Autophagy Ameliorates Neuromuscular-Associated Defects and Extends Lifespan in a Caenorhabditis elegans Model of Spinal Muscular Atrophy,” was published in ACS Chemical Neuroscience.

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Autophagy activators led to improvements in survival

SMA is a genetic disease caused mainly by mutations that lead to low levels of a protein called SMN. Lacking SMN, motor neurons — the nerve cells that govern movement — sicken and die. Although it’s well-established that low SMN protein levels drive motor neuron death in SMA, the exact biological mechanisms by which SMN deficiency causes motor neuron problems are not fully understood.

Autophagy — derived from Greek words that literally mean “self-eating” — is a form of molecular recycling, where cells break down complex molecular structures into simple components that can be repurposed. Previous studies have suggested that autophagy is dysregulated in SMA, but the relevance of autophagy in this disease remains unclear.

“It remains controversial whether autophagy activation or inhibition is ultimately beneficial,” the researchers wrote.

Caenorhabditis elegans, a type of nematode worm, is commonly used as a lab model because it has a simple nervous system and a short lifespan. Here, a trio of scientists in the U.K. used a C. elegans model of SMA to explore the role of autophagy in this disease.

When considered together with our [SMN] data, these results suggest that autophagy activation exerts therapeutic benefit in the SMA model through an autophagy-dependent mechanism that may, at least in part, promote or stabilize residual [SMN] levels.

The researchers first treated SMA C. elegans with four different drugs that block autophagy. They found that these medications generally did not affect the worm’s neuromuscular function. No changes were found in SMN protein levels among the two autophagy inhibitors tested.

The researchers then tested four different drugs that can activate autophagy. This led to increases in measures of mobility, as well as statistically significant improvements in survival. Autophagy activators also increased SMN protein levels, which the researchers said likely explains the beneficial effects at least in part.

“When considered together with our [SMN] data, these results suggest that autophagy activation exerts therapeutic benefit in the SMA model through an autophagy-dependent mechanism that may, at least in part, promote or stabilize residual [SMN] levels,” the scientists wrote.

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Scientists called for further research into resveratrol

Notably, these improvements were specific to SMA nematodes: in healthy C. elegans, treatment with autophagy activators did not impact survival or mobility.

“The beneficial effects observed were specific to [the SMA model], as no [motor function] improvements were evident in control animals, indicating a targeted therapeutic response,” the researchers wrote.

Although all four autophagy-activating drugs that the researchers tested showed some promise in the SMA model, the researchers said that resveratrol is the most promising for further study, because it produced consistent effects at low doses without toxic effects in their models. The scientists called for further research into whether resveratrol or other autophagy-activating compounds may be useful for SMA treatment.

“Our study establishes pharmacological activation of autophagy as an effective strategy to ameliorate key disease-associated [traits] in a well-characterized C. elegans model of SMA. … These data demonstrate the therapeutic potential of targeting autophagic pathways as combinatorial treatment strategies for SMA,” the researchers wrote. “Importantly, given the high evolutionary conservation of autophagy and SMN-dependent pathways across species, these findings provide a biologically grounded framework that may inform translational efforts in mammalian systems.”