New research insights in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a hereditary disease that causes the death of nerve cells in the spinal cord in young children. This means that children with SMA have weak muscles and do not develop normal motor skills, such as sitting up or walking.

One of the molecular pathways that changes in SMA is the system responsible for recycling unwanted proteins. In SMA, the key disruption to this protein recycling pathway is a reduction in the levels of a particular protein, called ubiquitin-like modifier-activating enzyme 1 (UBA1). There are drugs that increase UBA1 protein levels and reverse muscle weakness and motor nerve degeneration in mice that have SMA. However, it is still unknown how low levels of UBA1 causes motor nerve degeneration in SMA.

In the current study the research team, led by Professor Tom Gillingwater, set out to investigate this further. They found that low levels of UBA1 affect the function of several other molecular pathways. This includes proteins from a pathway that causes another genetic disease, called Charcot-Marie-Tooth disease (CMT). Specifically, a protein called GARS which causes CMT type 2D, is changed in SMA. This disease is similar to SMA as it also causes death of motor nerves and weakness of muscles. Also, CMT type 2D patients have degeneration of sensory nerves that are used to touch and feel. The researchers found that changes to sensory nerves that occur in CMT type 2D are also present in mice that have SMA. Specifically, this was caused by changes in protein levels of GARS and UBA1.

There are many types of neuromuscular disease such as CMT and SMA that occur very infrequently. Because of this, it is important to investigate if overlap exists in the molecular mechanisms that cause these diseases. This might mean that therapies that are developed for one specific disease might also be applied to others. In keeping with this, Professor Gillingwater’s team of researchers investigated the effect of increasing UBA1 protein levels in SMA mice on GARS and sensory nerves. They found that this treatment reversed GARS protein levels and rescued the changes that happen to sensory nerves. This shows that rare neuromuscular diseases such as CMT and SMA might share common molecular causes that can be treated using the same drugs.

The study was published in the journal Brain. The research was funded by the Euan MacDonald Centre, the SMA Trust, the Wellcome Trust and SMA Europe.

Related links

Link to the full publication on the Brain website: "UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy". doi.org/10.1093/brain/awy237

Professor Tom Gillingwater's profile

Research theme: Understanding motor neurons