A team of scientists from the University of Malta and the Institut de Génétique Moléculaire de Montpellier (CNRS/Université de Montpellier) unveiled the pathway that, once faulty, triggers muscle weakness and paralysis in the leading motor neuron disease of infancy, spinal muscular atrophy (SMA). The newly obtained insights may be crucial for the development of treatment strategies for patients with one of the most catastrophic of human disorders.
SMA parallels amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, with both disorders robbing patients of their ability to walk, eat or breathe. While ALS has an adult onset, SMA strikes young children. SMA patients inherit a flaw in the Survival Motor Neuron (SMN) gene that decimates the levels of the SMN protein, causing motor neurons and the associated muscles to die. Awareness and fundraising drives to find a treatment for these cruel disorders keep hitting the airwaves in Malta thanks to Bjorn Formosa, a young and talented individual, whose ALS diagnosis shocked the nation.
The SMN protein has been implicated in the assembly of the splicing machinery that cuts and pastes the cell’s genetic instructions together. Whether this basic biological function is disrupted in SMA has remained unclear. Now, the research team discovered that the disruption of pICln and Tgs1, two chief players in the splicing machinery assembly pathway, leads to the collapse of the neuromuscular system of fruit flies in a similar manner to SMN deficiency. At a cellular level, making use of brewer’s yeast, the researchers observe a pathway that comes to a standstill. The breakthrough discovery, which was reported in the journal Neurobiology of Disease, implies that a failure to correctly process the genetic blueprint for the production of functional proteins is likely to blame for the neuromuscular deficits in SMA.
“Lines of therapeutic attack have been limited in SMA due to the lack of clarity on the pathway linking a deficiency in the SMN protein to the collapse of the neuromuscular system in patients,” said the study’s lead author Dr. Ruben J. Cauchi, a senior lecturer at the Department of Physiology and Biochemistry within the University of Malta’s Faculty of Medicine & Surgery, and principal investigator in the Centre for Molecular Medicine and Biobanking of the University of Malta. “Many are reluctant to blame a fault in the assembly of the splicing machine because it is difficult to reconcile with the fact that motor neurons and muscle cells die selectively in patients. Our study solves this mystery by demonstrating that the neuromuscular system is highly sensitive to disturbances in this critical pathway,” added Cauchi.
In view of strikingly similar symptoms, the hunch that ALS and SMA are linked proved to be correct as several studies have recently reported a convergence on the mechanisms underpinning both disorders. To this end, increasing evidence implicating perturbation in the splicing machinery in ALS leads one to believe that this pathway is central for a healthy neuromuscular system.
“A shared pathway translates into a common treatment” remarked Dr. Rémy Bordonne, CNRS principal investigator and study co-author. Right now the research team is expanding our knowledge of the pathway by identifying novel components that can possibly act as therapeutic targets that reverse the neuromuscular decline in both the incurable ALS and SMA. “The use of model organisms is vital for the successful conclusion of this exciting journey,” concluded Bordonne.
The research was funded by the University of Malta Faculty of Medicine & Surgery Dean’s Initiative, the Malta Council for Science & Technology, the Embassy of France to Malta, and a Malta Strategic Educational Pathways Scholarship (part-financed by the European Social Fund). Study co-authors from the University of Malta were Dr. Neville Vassallo, Rebecca Borg and Benji Fenech Salerno. The researchers dedicate, with admiration and affection, their four-year painstaking research efforts to the indefatigable Bjorn Formosa.
Borg, R.M., Fenech Salerno, B., Vassallo, N., Bordonne, R., & Cauchi, R.J. Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy, Neurobiol. Dis. (2016), http://dx.doi.org/10.1016/j.nbd.2016.06.015