Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Boyd, P.J., Tu, W.Y., Shorrock, H.K., Groen, E.J.N., Carter, R.N., Powis, R.A., Thomson, S.R., Thomson, D., Graham, L.C., Motyl, A.A.L., Wishart, T.M., Highley, J.R., Morton, N.M., Becker, T., Becker, C.G., Heath, P.R., Gillingwater, T.H.
PLoS Genetics   13: e1006744 (Journal)
Registered Authors
Becker, Catherina G., Becker, Thomas, Boyd, Penelope
Motor neurons, Zebrafish, Mitochondria, Embryos, Gene pool, Axons, Bioenergetics, Spinal cord
MeSH Terms
  • Adenosine Triphosphate/metabolism
  • Animals
  • Axons/metabolism
  • Axons/pathology
  • Disease Models, Animal
  • Disease Susceptibility
  • Energy Metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Mitochondria/metabolism
  • Motor Neurons/drug effects
  • Motor Neurons/metabolism*
  • Muscle, Skeletal/metabolism
  • Muscle, Skeletal/pathology
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy, Spinal/metabolism*
  • Muscular Atrophy, Spinal/physiopathology
  • Phosphoglycerate Kinase/antagonists & inhibitors
  • Phosphoglycerate Kinase/genetics*
  • Prazosin/administration & dosage
  • Prazosin/analogs & derivatives
  • Spinal Cord/growth & development
  • Spinal Cord/metabolism*
  • Spinal Cord/pathology
  • Survival of Motor Neuron 1 Protein/genetics*
  • Survival of Motor Neuron 1 Protein/metabolism
  • Zebrafish/genetics
  • Zebrafish/growth & development
28426667 Full text @ PLoS Genet.
Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes