Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.

Keywords: autophagic flux; autophagy; macroautophagy; mitophagy; spinal muscular atrophy.

FIGURE 1

SMA associated genes SMN1 and SMN2 on human chromosome 5. SMA patients display deletions or mutations in both copies of SMN1; although SMN2 is expressed, most of the SMN2 mRNA transcripts lack exon 7 due to a C > T nucleotide change. Thus, most of the product deriving from the SMN2 gene is mostly unstable and rapidly degraded (SMNΔ7).

FIGURE 2

Three main forms of autophagy. (A) Macroautophagy is characterized by engulfment and transfer of cargo to lysosomes via an intermediary double membrane vesicle. (B) Microautophagy is characterized by direct invagination of cytoplasmic material into the lysosome. (C) Chaperone-mediated autophagy involves delivery of cargo marked by the Hsc70 chaperone complex to the lysosome via the LAMP2A receptor.

FIGURE 3

Main steps of macroautophagy. The pathway begins with the initiation step in which mTOR dissociates from the ULK1/2-ATG13-FIP200 autophagy induction complex in order for the phagophore to be formed. Subsequently, nucleation of the phagophore is orchestrated by a PI3K complex composed of Beclin 1, VPS34, VPS15 and ATG14. As the vesicle elongates, LC3 undergoes proteolytic cleavage by ATG4 into LC3-I. LC3-I is then bound by ATG7 and ATG3 and finally conjugated by phosphatidylethanolamine (PE); the resultant form is known as LC3-II. Once LC3-II incorporates into the autophagosome membrane, the extending ends join, engulfing cellular cargo. During the process, p62 delivers ubiquitinated cargo to the autophagosome where it binds with LC3-II. The autophagosome is then transported along microtubules to the lysosome which will dock and fuse through the action of small GTPases, SNAREs and the HOPS complex/EPG5 tethering factors. Cellular cargo then undergoes lysosomal degradation and dismantled components are recycled.

FIGURE 4

Autophagy in healthy and SMA motor neurons. In healthy motor neurons autophagic stimuli would lead to an increased mitophagy/autophagic activity, degradation and recycling of cellular cargo. In SMA motor neurons, decreased SMN levels result in dysfunctional mitochondria, reduced autophagic activity and downregulation of lysosomal gene expression. These aberrations drive autophagosome accumulation and diminished autophagic flux, potentially leading to apoptotic and non-apoptotic cell death in motor neurons of SMA patients.