Combined approach improves nerve cell communication in SMA lab study
Researchers restored SMN protein and used forskolin to improve cell function
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- SMN protein deficiency damages motor neurons, while astrocyte abnormalities may further disrupt nerve cell communication in SMA.
- SMA astrocytes showed abnormal shapes and fewer extensions, while cultures containing SMA motor neurons had fewer detected synapses.
- Combining SMN restoration in astrocytes with forskolin improved cell structure, synapses, and motor neuron electrical activity in lab experiments.
Combining two approaches to address problems in astrocytes, cells that support nerve cells (neurons), may improve communication between motor neurons in spinal muscular atrophy (SMA), a new study suggests.
Researchers increased levels of SMN, the protein deficient in SMA, in lab-grown astrocytes derived from patients. They also used forskolin, a compound that promotes changes in actin, a protein that helps cells maintain and change their shape.
Each approach, used alone or together, improved certain problems in astrocytes and increased the number of detected connections between motor neurons derived from people with SMA. Combining the approaches also improved aspects of motor neuron electrical activity that neither approach improved on its own.
The findings suggest that targeting both SMN deficiency and actin-related abnormalities may help improve motor neuron function and other disease-related problems in SMA, the researchers wrote.
Study explores ways to improve motor neuron function in SMA
The study, “Astrocyte SMN Restoration and Forskolin Treatment Improve SMA Synaptic Pathology,” was published in the Annals of Neurology.
SMA is primarily caused by mutations in the SMN1 gene, which lead to a shortage of the SMN protein. Without enough of this protein, motor neurons, the nerve cells that control movement, become damaged and die, leading to progressive muscle weakness, muscle wasting, and other symptoms of SMA.
Previous research has shown that astrocytes, which help keep nerve cells healthy and regulate how they communicate, can contribute to motor neuron dysfunction in SMA. These cells have tiny, finger-like extensions called perisynaptic astrocyte processes (PAPs), which help maintain synapses, or connections between nerve cells. Problems with synapses are among the earliest changes seen in SMA.
Previous laboratory studies have shown that restoring SMN specifically in astrocytes leads to only limited improvements in motor neuron function. This suggests that other disease-related problems may also need to be addressed.
One possibility involves actin, which helps form the extensions astrocytes use to support synapses. Although SMN helps regulate actin, previous research has shown that targeting certain actin-related proteins and signaling pathways can reduce disease severity independently of SMN.
“Therefore, developing combined treatment strategies to target SMN-dependent and related disease-relevant mechanisms may enhance therapeutic efficacy,” the researchers wrote.
Researchers test combined approach in lab-grown cells
With this in mind, researchers in the U.S. tested whether combining SMN restoration in astrocytes with forskolin could improve motor neuron function. Forskolin increases levels of a signaling molecule called cyclic AMP (cAMP), which can stimulate changes in actin.
They generated astrocytes and motor neurons from induced pluripotent stem cells (iPSCs) obtained from people with SMA and healthy individuals. These stem cells can develop into different cell types.
The team first examined astrocytes grown alone. Compared with healthy cells, SMA astrocytes appeared enlarged and swollen and had fewer tiny extensions. Unlike healthy astrocytes, they did not produce more extensions when stimulated to change their structure. They also had lower levels of several proteins involved in regulating actin.
Researchers then grew astrocytes alongside motor neurons. Cultures containing SMA cells had fewer synapses and lower levels of certain proteins associated with PAPs, which normally surround and support these connections.
The team next tested whether the dual approach could improve astrocyte function and benefit motor neurons. They used a modified virus to deliver a working copy of the SMN1 gene to SMA astrocytes, allowing the cells to produce more SMN protein. The researchers also tested forskolin alone and in combination with SMN restoration.
In astrocytes grown alone, forskolin increased the number of tiny extensions, although the cells remained enlarged compared with healthy astrocytes. Restoring SMN also increased the number of extensions. When the researchers stimulated the astrocytes to remodel their structure, combining both approaches led to more extensive branching and changes in cell shape.
Combined approach improves communication between motor neurons
In cultures containing both astrocytes and motor neurons, each approach, alone or combined, increased the number of detected synapses compared with untreated SMA cultures.
The treatments also improved motor neuron electrical activity. Compared with healthy motor neurons, those derived from people with SMA fired electrical signals more frequently in response to stimulation. This abnormal activity was reduced in all three treatment conditions.
The combination treatment, however, produced additional benefits. Only motor neurons grown alongside SMN-restored astrocytes and treated with forskolin showed spontaneous bursts of coordinated electrical activity across the cell network, indicating improved communication between nerve cells.
The combined treatment also restored the amount of electrical current needed to activate SMA motor neurons to levels comparable to those in healthy motor neurons.
The study “provides proof-of-concept evidence that combined SMN restoration and cAMP/actin modulation” can improve certain disease-related abnormalities within motor neurons themselves and those involving other cells, the researchers wrote.
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