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LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy

View ORCID ProfileS Nichterwitz, View ORCID ProfileH Storvall, View ORCID ProfileJ Nijssen, View ORCID ProfileLH Comley, View ORCID ProfileI Allodi, M van der Lee, View ORCID ProfileC Schweingruber, View ORCID ProfileQ Deng, View ORCID ProfileR Sandberg, E Hedlund
doi: https://doi.org/10.1101/356113
S Nichterwitz
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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  • For correspondence: eva.hedlund@ki.se susanne.nichterwitz@gmail.com
H Storvall
2Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
3Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden
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J Nijssen
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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LH Comley
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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I Allodi
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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M van der Lee
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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C Schweingruber
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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Q Deng
3Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden
4Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
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R Sandberg
2Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
3Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden
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E Hedlund
1Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
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  • For correspondence: eva.hedlund@ki.se susanne.nichterwitz@gmail.com
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Abstract

Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), a lethal disease caused by a deficiency of the ubiquitously expressed survival of motor neuron (SMN) protein. However, some brainstem motor neuron groups, including oculomotor and trochlear (ocular), which innervate the muscles around the eyes, are for unknown reasons spared. Here, using laser capture microdissection coupled with RNA sequencing (LCM-seq), we investigate the transcriptional dynamics in discrete neuronal populations in health and SMA to reveal mechanisms of vulnerability and resistance. Using gene correlation network analysis, we reveal a p53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in resistant red nucleus and visceral motor neurons. However, our temporal and spatial differential expression analysis across neuron types clearly demonstrates that the majority of SMA-induced modulations are cell-type specific. Notably, using gene ontology and protein-network analyses we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. In particular, ocular motor neurons up-regulate; i) Syt1, Syt5 and Cplx2, which modulate neurotransmitter release; ii) the motor neuron survival factors Chl1 and Lif, iii) Aldh4, that can protect cells from oxidative stress and iv) the caspase inhibitor Pak4. In conclusion, our in-depth longitudinal analysis of gene expression changes in SMA reveal novel cell-type specific changes that present compelling targets for future gene therapy studies aimed towards preserving vulnerable motor neurons.

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Posted June 27, 2018.
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LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy
S Nichterwitz, H Storvall, J Nijssen, LH Comley, I Allodi, M van der Lee, C Schweingruber, Q Deng, R Sandberg, E Hedlund
bioRxiv 356113; doi: https://doi.org/10.1101/356113
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LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy
S Nichterwitz, H Storvall, J Nijssen, LH Comley, I Allodi, M van der Lee, C Schweingruber, Q Deng, R Sandberg, E Hedlund
bioRxiv 356113; doi: https://doi.org/10.1101/356113

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