Protein Disruption May Lead to New Treatments for Motor Neuron Diseases

Research sheds light on the mechanism behind the development of spinal muscular atrophy (SMA).

In a new study, the disruption of key cellular proteins that help assemble the splicing machinery caused the neuromuscular system of fruit flies to collapse in a manner similar to patients with spinal muscular atrophy (SMA), revealing the mechanism that explains how motor neuron disease develops.

SMA is a motor neuron disease the effects the cells in the brain and spinal cord, causing patients to lose their ability to walk, speak, swallow, and breathe. Symptoms are similar to that of amyotrophic lateral sclerosis (ALS), which mostly affects adults, while SMA mostly affects young children.

In SMA, patients inherit a flaw in the Survival Motor Neuron (SMN) gene that decimates the levels of SMN protein, causing motor neurons to die, and muscles to atrophy. It’s been found that the SMN protein plays a role in the assembly of the splicing machinery that cuts and pastes the cell’s genetic instructions together.

However, it was unclear if this basic biological function was disrupted in SMA. In a new study published in Neurobiology of Disease, researchers found that the disruption of cellular proteins pICIn and Tgs1, two key players that help assemble the splicing machinery, caused the fruit flies’ neuromuscular system to collapse in a similar manner to patients with SMA.

The findings implicate that the failure to correctly process the genetic blueprint that produces correctly working proteins is most likely to blame for the neuromuscular deficits in young patients with motor neuron disease.

“Therapies have been difficult to develop because of the lack of clarity on how a shortage of the SMN protein leads to motor neuron death and muscle weakness in patients,” said lead study author Ruben J. Cauchi, PhD.

According to the study, the splicing machinery is essential for the health of all cells. However, when there is a shortfall in the SMN protein in flies and humans, only the motor neurons and muscles cells are effected, and begin to die off, while a majority of the others survive.

“Our study solves this mystery by showing that the motor neurons and muscles are highly sensitive to disturbances in the assembly of the splicing machine, consequently leading to them being selectively injured,” said Cauchi.

It’s been hypothesized that ALS and SMA are related because of the similarities in symptoms. This was proven to be true in numerous studies that showed the same cellular mechanisms supported both disorders.

Additionally, in most ALS patients, the splicing machinery is found to be severely hit.

“A shared mechanism translates into a common treatment,” said principal investigator and study co-author Rémy Bordonne, PhD.

Currently, further analysis of the disease mechanism is being conducted to help guide researchers on a path towards treatment of motor neuron diseases.