SMA tied to organ-specific redox imbalances in mouse study
Antisense therapy partly restored redox balance in some organs
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- SMA involves multi-organ redox changes, including reduced S-glutathionylation, a protective protein modification.
- These changes affect organs like the spinal cord, heart, and liver, varying by tissue and disease stage.
- ASO treatment partly improved this modification in some organs, highlighting SMA’s systemic effects.
Spinal muscular atrophy (SMA) is associated with multi-organ changes in a protective protein modification that helps guard cells against molecular damage, according to a study in mice.
The researchers also found that treatment with antisense oligonucleotides — the same type of SMN-targeting approach used in Spinraza (nusinersen) — partly improved levels of this modification in some organs, but not others. The findings add to growing evidence that SMA affects more than motor neurons, highlighting the need to better understand how the disease impacts different tissues throughout the body.
The study, “Organ-specific redox imbalances in spinal muscular atrophy mice are partially rescued by SMN antisense oligonucleotides,” was published in FEBS Letters.
How SMN deficiency affects cells beyond motor neurons
SMA is a genetic disorder caused mainly by mutations in the gene that provides instructions for making the SMN protein. When SMN levels are low, motor neurons — the nerve cells that control movement — become damaged and eventually die.
Although it’s well-established that low SMN levels drive SMA, scientists are still working to understand exactly how this deficiency affects cells at the molecular level. Less is known about how this deficiency affects cells outside the nervous system.
In this study, researchers in Germany used a mouse model to examine how SMN deficiency affects a protein modification called S-glutathionylation.
S-glutathionylation involves attaching a small molecule to proteins. This modification helps protect cells from oxidative stress, a form of damage caused by highly reactive molecules that are naturally produced when cells generate energy.
The researchers found reduced S-glutathionylation in several organs of the SMA mice. In the spinal cord, heart, and liver, levels were lower at early disease stages and declined further as the disease progressed. In the brain, levels appeared normal early on but were reduced at later stages. In contrast, levels in the gastrocnemius (a large calf muscle) remained within normal ranges even in late-stage SMA mice.
These findings suggest that SMA is “characterized by systemic dysregulation of protein S-glutathionylation,” the researchers wrote. However, they noted that this dysregulation “does not follow a uniform trajectory across organs but instead reflects intrinsic tissue-specific … vulnerabilities [to oxidative stress].”
Heart findings suggest ferroptosis-related changes
In the heart, reduced S-glutathionylation was accompanied by lower levels of an antioxidant enzyme. The researchers said this pattern was consistent with changes seen in ferroptosis, a form of iron-dependent cell death that can be triggered by oxidative stress. The team suggested this type of cell damage could potentially contribute to heart complications in SMA, but emphasized that further studies are needed.
The researchers then tested an antisense oligonucleotide designed to increase SMN protein levels. Treatment was associated with higher S-glutathionylation levels in the heart and brain compared with untreated SMA mice. However, levels in the spinal cord were not significantly changed.
“Altogether, these results indicate that [antisense oligonucleotide] therapy increased SMN levels only mildly and at different magnitudes across the tested organs,” the researchers wrote.
The scientists said the findings “broaden the mechanistic landscape of SMA beyond … motor neuron loss” and suggest that “S-glutathionylation dynamics [are] central but context-dependent components” of SMA disease biology.
