PLoS genetics, 2017-04, Vol.13 (4), p.e1006744-e1006744
2017
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- Autor(en) / Beteiligte
- Titel
- Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy
- Ist Teil von
- PLoS genetics, 2017-04, Vol.13 (4), p.e1006744-e1006744
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7404, 1553-7390eISSN: 1553-7404DOI: 10.1371/journal.pgen.1006744Titel-ID: cdi_plos_journals_1899331415
- Format
- –
- Schlagworte
- Adenosine Triphosphate - metabolism, Amyotrophic lateral sclerosis, Animals, Axons - metabolism, Axons - pathology, Bioenergetics, Biology and Life Sciences, Cell survival, Comparative analysis, Degeneration, Development and progression, Disease Models, Animal, Disease resistance, Disease Susceptibility, Energy Metabolism, Gene expression, Gene Expression Regulation, Developmental, Genetic aspects, Humans, Medicine and Health Sciences, Mice, Mitochondria, Mitochondria - metabolism, Motor neurons, Motor Neurons - drug effects, Motor Neurons - metabolism, Motor task performance, Muscle, Skeletal - metabolism, Muscle, Skeletal - pathology, Muscles, Muscular Atrophy, Spinal - genetics, Muscular Atrophy, Spinal - metabolism, Muscular Atrophy, Spinal - physiopathology, Neuromuscular diseases, Neurosciences, Phosphoglycerate kinase, Phosphoglycerate Kinase - antagonists & inhibitors, Phosphoglycerate Kinase - genetics, Phosphoglycerate kinase 1, Physiological aspects, Prazosin - administration & dosage, Prazosin - analogs & derivatives, Research and Analysis Methods, Rodents, Skeletal muscle, SMN protein, Spinal Cord - growth & development, Spinal Cord - metabolism, Spinal Cord - pathology, Spinal muscular atrophy, Survival of Motor Neuron 1 Protein - genetics, Survival of Motor Neuron 1 Protein - metabolism, Vulnerability, Zebrafish, Zebrafish - genetics, Zebrafish - growth & development