LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy

Susanne Nichterwitz, Jik Nijssen, Helena Storvall, Christoph Schweingruber, Laura Helen Comley, Ilary Allodi, Mirjam van der Lee, Qiaolin Deng, Rickard Sandberg, Eva Hedlund

Research output: Contribution to journalArticlepeer-review

Abstract

Somatic motor neurons are selectively vulnerable in spinal muscular atrophy (SMA), which is caused by a deficiency of the ubiquitously expressed survival of motor neuron protein. However, some motor neuron groups, including oculomotor and trochlear (ocular), which innervate eye muscles, are for unknown reasons spared. To reveal mechanisms of vulnerability and resistance in SMA, we investigate the transcriptional dynamics in discrete neuronal populations using laser capture microdissection coupled with RNA sequencing (LCM-seq). Using gene correlation network analysis, we reveal a TRP53-mediated stress response that is intrinsic to all somatic motor neurons independent of their vulnerability, but absent in relatively resistant red nucleus and visceral motor neurons. However, the temporal and spatial expression analysis across neuron types shows that the majority of SMA-induced modulations are cell type-specific. Using Gene Ontology and protein network analyses, we show that ocular motor neurons present unique disease-adaptation mechanisms that could explain their resilience. Specifically, ocular motor neurons up-regulate (1) Syt1, Syt5, and Cplx2, which modulate neurotransmitter release; (2) the neuronal survival factors Gdf15, Chl1, and Lif; (3) Aldh4, that protects cells from oxidative stress; and (4) the caspase inhibitor Pak4. Finally, we show that GDF15 can rescue vulnerable human spinal motor neurons from degeneration. This confirms that adaptation mechanisms identified in resilient neurons can be used to reduce susceptibility of vulnerable neurons. In conclusion, this in-depth longitudinal transcriptomics analysis in SMA reveals novel cell type-specific changes that, alone and combined, present compelling targets, including Gdf15, for future gene therapy studies aimed toward preserving vulnerable motor neurons.

Original languageEnglish
Pages (from-to)1083-1096
Number of pages14
JournalGenome Research
Volume30
Issue number8
DOIs
Publication statusPublished - Aug 2020

Keywords

  • Adaptation, Physiological/genetics
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Eye/innervation
  • Genetic Predisposition to Disease/genetics
  • Growth Differentiation Factor 15/genetics
  • Laser Capture Microdissection
  • Mice
  • Mice, Knockout
  • Motor Cortex/pathology
  • Motor Neurons/metabolism
  • Muscular Atrophy, Spinal/genetics
  • Neuroprotection/genetics
  • Sequence Analysis, RNA
  • Survival of Motor Neuron 1 Protein/genetics
  • Survival of Motor Neuron 2 Protein/genetics
  • Transcriptional Activation/genetics
  • Tumor Suppressor Protein p53/genetics

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