Targeting JNK pathway may offer new treatment approach for SMA
Targeting a stress-activated signaling pathway may offer a new way to treat spinal muscular atrophy (SMA), either on its own or in combination with existing therapies.
Researchers found that blocking the c-Jun N-terminal kinase (JNK) pathway with medications significantly reduced disease severity and extended survival in a mouse model of severe SMA.
Unlike approved SMA therapies, which work by increasing levels of the survival motor neuron (SMN) protein — which is low in people with the disease — JNK inhibition targets downstream processes caused by this deficiency that lead to the degeneration of motor neurons. These specialized nerve cells control movement and are progressively lost in the disease.
“These findings suggest that pharmacological inhibition of JNK may serve as a therapeutic strategy to prevent neurodegeneration,” the researchers wrote, adding that it could be used either in combination with SMN-targeting therapies for severe forms of SMA, “or as a stand-alone, SMN-independent intervention” for milder forms of the disease.
JNK pathway identified as potential target in SMA
The study, “Survival motor neuron protein-independent amelioration of spinal muscular atrophy by pharmacological inhibition of c-Jun-NH2 terminal kinase,” was published in Brain Communications.
SMA is mainly caused by mutations that lead to a shortage of the SMN protein, which is essential for the health of motor neurons. As these neurons become damaged and die, patients may develop symptoms such as muscle weakness and muscle wasting.
While approved therapies that boost SMN levels have significantly improved outcomes for people with SMA, important challenges remain. These include differences in how patients respond, the timing of treatment, and the need to address symptoms that affect multiple organs and tissues beyond motor neurons.
Evidence from preclinical and clinical studies suggests that fully and durably treating SMA may require combining SMN-targeting therapies with other approaches that work independently of SMN and target other disease-driving mechanisms.
One such mechanism is activation of the JNK signaling pathway, which has been linked to the degeneration of neurons lacking enough SMN. Earlier studies showed that blocking this pathway, especially by targeting the neuron-specific form JNK3, could reduce disease severity in SMA mice without changing SMN protein levels.
Researchers test JNK inhibitors in SMA models
Here, researchers set out to further explore whether targeting the JNK signaling pathway could help treat SMA. They first screened 20 JNK inhibitors for low toxicity, narrowing the list to eight compounds for further testing.
To identify the most effective ones, these eight compounds were tested in primary mouse cerebellar neurons, where SMN levels had been reduced to trigger JNK activation and neuron degeneration.
Of those eight, three stood out for their ability to reduce JNK activity and protect SMN-deficient neurons: anthrapyrazolone (SP600125), pyrimidinyl (AS601245), and pyridopyrimidine (SR12519), which target different forms of JNK.
When tested in motor neurons derived from the spinal cord of SMA mice, the cells most affected in the disease, all three compounds reduced JNK activation and improved cell survival and growth compared with untreated cells. These findings suggest “that inhibition of JNK signalling is a critical requirement for preventing the degeneration of SMN-deficient motor neurons in SMA,” the researchers wrote.
The researchers then tested the three lead compounds in a severe SMA mouse model. Treatment began two days after birth and was given every other day. Across all three compounds, JNK inhibition improved disease outcomes compared with untreated controls.
JNK inhibition improves survival, motor function in mice
Survival and growth improved in each treatment group. Across treatments, survival increased about twofold compared with controls. Growth also improved significantly across all treatment groups, as shown by increases in body weight and the length of time mice continued to grow after birth. These benefits were observed in both sexes, although pyrimidinyl showed greater effects in male mice.
Motor performance and muscle strength also improved across all treatment groups. Treated mice showed a better ability to stand, walk, and right themselves after being placed on their backs. They also performed better in the hind-limb suspension test, which measures how long mice can hang by their hind legs before falling, indicating stronger muscle function.
At the molecular level, all three compounds lowered levels of phosphorylated c-Jun — a marker of JNK pathway activation — in the spinal cord. In skeletal muscle, however, only the broader JNK inhibitors (anthrapyrazolone and pyrimidinyl) significantly reduced JNK activity, while the more selective pyridopyrimidine had no effect. None increased SMN protein levels in the spinal cord or skeletal muscle, supporting the conclusion that their protective effects were independent of SMN.
Overall, the findings of this study “establish a proof-of-concept that the pharmacological inhibition of JNK is a viable SMN-independent method for neuroprotection and the treatment of SMA,” the researchers concluded. “These findings should allow the development of suitable standalone and combination therapeutic strategies involving SMN level enhancement for the treatment of mild to severe forms of SMA.”
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