In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology
Paola Bernabò,
Toma Tebaldi,
Ewout J.N. Groen,
Fiona M. Lane,
Elena Perenthaler,
Francesca Mattedi,
Helen J. Newbery,
Haiyan Zhou,
Paola Zuccotti,
Valentina Potrich,
Hannah K. Shorrock,
Francesco Muntoni,
Alessandro Quattrone,
Thomas H. Gillingwater,
Gabriella Viero
Affiliations
Paola Bernabò
Institute of Biophysics, CNR Unit at Trento, Via Sommarive 18, 38123 Povo (Trento), Italy
Toma Tebaldi
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy
Ewout J.N. Groen
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK
Fiona M. Lane
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK
Elena Perenthaler
Institute of Biophysics, CNR Unit at Trento, Via Sommarive 18, 38123 Povo (Trento), Italy
Francesca Mattedi
Institute of Biophysics, CNR Unit at Trento, Via Sommarive 18, 38123 Povo (Trento), Italy
Helen J. Newbery
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK
Haiyan Zhou
Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London 30, Guilford Street, WC1N 1EH London, UK
Paola Zuccotti
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy
Valentina Potrich
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy
Hannah K. Shorrock
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK
Francesco Muntoni
Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London 30, Guilford Street, WC1N 1EH London, UK
Alessandro Quattrone
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123 Povo (Trento), Italy; Corresponding author
Thomas H. Gillingwater
Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, EH8 9XD Edinburgh, UK; Corresponding author
Gabriella Viero
Institute of Biophysics, CNR Unit at Trento, Via Sommarive 18, 38123 Povo (Trento), Italy; Corresponding author
Summary: 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 SMN dependent. 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. : Bernabò et al. analyzed translation in a mouse model of spinal muscular atrophy and identified translation defects that arise early in pathogenesis, are cell autonomous, and are accompanied by a low number of axonal ribosomes in diseased nerves. Their findings highlight ribosome biology as a central hallmark of the disease. Keywords: neurodegeneration, motor neuron disease, ribosome, translatome, polysomal profiling, spinal muscular atrophy, SMN