New Study Improves Understanding of Impaired SMA Pathway

08 November 2019

To continue to develop new, specialised therapies for SMA, it is vital that we improve our understanding of why motor nerves die in the disease and continue to pursue all possible therapeutic options. The more we know about how reduced SMN levels affect the human body, the more genes / proteins that we can potentially target to reduce symptoms (click here for more information on the example of UBA1).

Chondrolectin is one such protein that is known to be altered at a very early stage in motor nerves of SMA mice (click here for more information). Since chondrolectin is found in the lower motor neurons of several vertebrates, including humans, it has been suggested that chondrolectin alterations may be playing a key role in SMA.

Indeed, past research has found that increasing the amount of available chondrolectin in zebrafish modelling SMA, can significantly improve the survival, growth and development of their motor neurons (click here for more information).

However, the function of chondrolectin in healthy nerve cells is poorly understood. It is therefore unclear how increasing chondrolectin improved motor neuron health in SMA zebrafish.

A new study published in the journal Cell Reports has begun to address these issues.

Prof. Catherina Becker (University of Edinburgh), in collaboration with Prof. Kevin Talbot (University of Oxford), has identified an important role for chondrolectin in the nervous system of both zebrafish and mice.

To do so, zebrafish and mice were genetically engineered to remove the chondrolectin gene causing no chondrolectin protein to be made. These genetic models were then studied to assess the effects of the absence of chondrolectin. By studying what happens when chondrolectin is missing, we can get an idea of its normal function.

In zebrafish, chondrolectin loss did not cause a major body-wide effect, but it did stunt the growth of motor neurons coming from the spinal cord. It also impaired the formation of the specialised connections between the motor neurons and other cells. This, in turn, was shown to impact the motor function of zebrafish without chondrolectin.

Similar results were shown in mice – chondrolectin loss impaired the growth and function of motor neurons and altered the connection between motor neurons and muscles known as the neuromuscular junction.

To carry out its essential functions, chondrolectin was shown to interact with a specific protein at the neuromuscular 
junction, stabilising this specialised part of motor neurons.

Given that chondrolectin levels are affected in SMA mice and that SMA mice show impaired neuromuscular junction connections, it is possible that chondrolectin may be contributing to this neuromuscular dysfunction in the disease.

Targeting chondrolectin may therefore provide a beneficial accessory therapy for SMA, by helping to stabilise and strengthen the connection of lower motor neurons to their muscles.
 

Further Information

Chondrolectin study published in Cell Reports