Journal
CELL REPORTS
Volume 21, Issue 4, Pages 953-965Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.10.010
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Funding
- Provincia Autonoma di Trento, Italy (AxonomiX research project)
- Wellcome Trust
- UK SMA Research Consortium (SMA Trust)
- Muscular Dystrophy UK
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
- UCL Therapeutic Innovation fund
- Wellcome Trust [106098/Z/14/Z] Funding Source: Wellcome Trust
- Great Ormond Street Hospital Childrens Charity [V0216] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10022] Funding Source: researchfish
- Wellcome Trust [106098/Z/14/Z] Funding Source: researchfish
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Genetic alterations impacting ubiquitously expressed proteins involved in RNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translation defects can contribute to disease. Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, whose role in pathogenesis remains unclear. Here, we identified in vivo and in vitro translation defects that are cell autonomous and SMNdependent. By determining in parallel the in vivo transcriptome and translatome in SMA mice, we observed a robust decrease in translation efficiency arising during early stages of disease. We provide a catalogue of RNAs with altered translation efficiency, identifying ribosome biology and translation as central processes affected by SMN depletion. This was further supported by a decrease in the number of ribosomes in SMA motor neurons in vivo. Overall, our findings suggest ribosome biology as an important, yet largely overlooked, factor in motor neuron degeneration.
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