Stabilizing cell connections eases motor dysfunction in mouse model
But use of gene therapy did not prolong overall survival in ALS model
![An oversized human hand holds a mouse next to rack of test tubes in a lab.](https://alsnewstoday.com/wp-content/uploads/2022/06/MouseHand.png)
A gene therapy aimed at stabilizing connections between motor nerve cells and interneurons — a type of cell that regulates motor nerve cell activity — eased motor dysfunction and promoted motor nerve cell survival in a mouse model of amyotrophic lateral sclerosis (ALS), according to a study by European scientists.
The treatment was designed to increase activity of the Esyt1 gene, which is important for stabilizing connections, or synapses, between these cell types.
Still, the effort did not prolong overall survival in the mouse model, the researchers noted.
“Altogether, these results indicate that motor impairment in SOD1G93A mice [an ALS mouse model] can be attenuated by stabilization of synaptic inputs between V1 interneurons and motor neurons,” the team wrote, adding that this approach might also help to stabilize other types of nerve cell connections.
The findings demonstrate “that interneurons can be a target to attenuate ALS symptoms,” the scientists noted.
The study, “Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS,” was published in the journal Nature Communications.
Negative results nonetheless highlight importance of cell connections
ALS is characterized by the progressive loss of motor neurons, the specialized nerve cells that communicate with muscles to coordinate movement. This leads to weakness in the muscles needed to move, swallow, speak, and breathe.
Motor neurons don’t work alone — they are part of complex nerve networks through which their activation is carefully coordinated. Nerve cells called interneurons act as relay stations in these networks to make sure motor neurons are activated or inhibited at the right time.
It’s been proposed that dysfunction of certain inhibitory interneurons, or ones that put the brakes on motor neuron activation, may play a role in ALS. The idea is that if motor neurons are not well-controlled by inhibitory interneurons, they will become overly excitable and this can cause toxicity.
The team of scientists previously had identified that a certain type of inhibitory interneurons called V1 lost their synapses with motor neurons in a mouse model of ALS, leading to movement problems.
Now, the scientists further explored the possible role of these V1 interneuron synapses in the same mouse model, and investigated whether stabilizing them could be a therapeutic approach for slowing disease progression.
These ALS mice were found to have reduced activity of the Esyt1 gene in both neurons and V1 interneurons of the spinal cord early on in the disease course. This gene encodes production of the extended synaptotagmin 1, or Esyt1, protein, which is important for stabilizing synapses.
Given that finding, the researchers investigated whether a gene therapy to increase Esyt1 gene activity in V1 interneurons, and thus Esyt1 protein levels, might restore better connectivity between motor neurons and V1 interneurons.
While this is not the hoped outcome, we believe that these negative results highlight the importance of other neural circuits affected in [the] disease that might play a pivotal role and should be considered when interpreting our results.
Indeed, the approach led to a restoration of functional inhibitory synapses between motor neurons and interneurons in the spinal cord, and further led to an increase in the survival rates of motor neurons overall.
Importantly, these cellular changes were also accompanied by long-term improvements in motor function in the mouse model, including increased speed, step frequency, and stride length, as well as some restoration of limb coordination and a greater ability to support the body during movement.
The scientists tested two different methods to deliver the gene therapy: either injected directly into the spine or given systemically into the bloodstream. The systemic approach led to more significant improvements in motor function and was generally safe.
Despite these improvements, increasing Esyt1 gene activity did not prevent weight loss, and thus, could not prolong survival in the ALS model.
“While this is not the hoped outcome, we believe that these negative results highlight the importance of other neural circuits affected in [the] disease that might play a pivotal role and should be considered when interpreting our results,” the researchers wrote.
Nevertheless, “the present work … indicates that the V1 interneurons-motor neuron circuit can be a potential target for treatment of spinal motor dysfunctions in ALS,” the team wrote.
In the future, the scientists plan to conduct more studies to understand whether the approach can be translated into a therapeutic strategy for use in humans, and if so, when would be the optimal timing for the treatment in a clinical setting.