Autophagy and Spinal Muscular Atrophy: Towards a Pathway-Centric Therapy for a Fatal Childhood Disorder

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular and the primary cause of infant death. SMA is characterised by the loss of motor neurons in the spinal resulting in progressive muscle atrophy, paralysis and respiratory defects leading to early childhood death. SMA is caused by a depletion of the ubiquitously expressed survival motor neuron (SMN) protein that performs a key regulatory function in the assembly of the eukaryotic mRNA splicing machinery and is thus required for the survival of all tissues. The genetic elements responsible for SMA are very well characterised but, after decades of research, it is still unknown why depletion of this ubiquitous specifically affects motor neurons. Numerous studies are now emerging that implicate disruption of autophagy, a highly conserved lysosomal degradative pathway responsible for the bulk removal of cytosolic cargo too large for the proteasome, in the disease pathology of SMA. In the present study, we utilise the powerful genetic tools of a Caenorhabditis elegans SMA model to delineate how disruptions in the autophagic pathway may contribute to SMA pathogenesis. Using an RNA interference genetic screen, we identified three putative modifiers of SMN loss of function neuromuscular defects in the C. elegans SMA model – epg-8, sqst-1 and atg-16.1. In line with pre-existing studies, our results indicate that autophagy is disrupted in SMA, and that this disruption is likely occur during the initial regulatory stages of the pathway. Although further study will be required to identify the precise mechanisms through which this autophagic disruption occurs, these findings show that autophagy has promising potential for novel therapeutic targets.