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Gene Expression Signatures of Sporadic ALS Motor Neuron Populations

View ORCID ProfileRanjan Batra, Kasey Hutt, Anthony Vu, Stuart J. Rabin, Michael W. Baughn, Ryan T. Libby, Shawn Hoon, John Ravits, Gene W. Yeo
doi: https://doi.org/10.1101/038448
Ranjan Batra
1Department of Cellular and Molecular Medicine, Stem cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
2Department of Neurosciences, University of California at San Diego, La Jolla
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  • ORCID record for Ranjan Batra
Kasey Hutt
1Department of Cellular and Molecular Medicine, Stem cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Anthony Vu
1Department of Cellular and Molecular Medicine, Stem cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Stuart J. Rabin
3Neurogenomics Lab, Benaroya Research Institute, Seattle, WA, USA
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Michael W. Baughn
2Department of Neurosciences, University of California at San Diego, La Jolla
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Ryan T. Libby
3Neurogenomics Lab, Benaroya Research Institute, Seattle, WA, USA
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Shawn Hoon
4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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John Ravits
2Department of Neurosciences, University of California at San Diego, La Jolla
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  • For correspondence: geneyeo@ucsd.edu jravits@ucsd.edu
Gene W. Yeo
1Department of Cellular and Molecular Medicine, Stem cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
2Department of Neurosciences, University of California at San Diego, La Jolla
4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
5Molecular Engineering Laboratory, A*STAR, Singapore
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  • For correspondence: geneyeo@ucsd.edu jravits@ucsd.edu
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Abstract

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily affecting motor neurons (MNs) to cause progressive paralysis. Ninety percent of cases are sporadic (sALS) and ten percent are familial (fALS). The molecular mechanisms underlying neurodegeneration remain elusive and there is a lack of promising biomarkers that define ALS phenotypes and progression. To date, most expression studies have focused on either complex whole tissues that contain cells other than MNs or induced pluripotent derived MNs (iMNs). Furthermore, as human tissue samples have high variability, estimation of differential gene-expression is not a trivial task.

Results Here, we report a battery of orthogonal computational analyses to discover geneexpression defects in laser capture microdissected and enriched MN RNA pools from sALS patient spinal cords in regions destined for but not yet advanced in neurodegenerative stage. We used total RNA-sequencing (RNA-seq), applied multiple percentile rank (MPR) analysis to analyze MN-specific gene-expression signatures, and used high-throughput qPCR to validate RNA-seq results. Furthermore, we used a systems-level approach that identified molecular networks perturbed in sALS MNs. Weighted gene co-expression correlation network (WGCNA) analysis revealed defects in neurotransmitter biosynthesis and RNA-processing pathways while gene-gene interaction analysis showed abnormalities in networks that pertained to cell-adhesion, immune response and wound healing.

Conclusions We discover gene-expression signatures that distinguish sALS from control MNs and our findings illuminate possible mechanisms of cellular toxicity. Our systematic and comprehensive analysis serves as a framework to reveal expression signatures and disrupted pathways that will be useful for future mechanistic studies and biomarker based therapeutic research.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 03, 2016.
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Gene Expression Signatures of Sporadic ALS Motor Neuron Populations
Ranjan Batra, Kasey Hutt, Anthony Vu, Stuart J. Rabin, Michael W. Baughn, Ryan T. Libby, Shawn Hoon, John Ravits, Gene W. Yeo
bioRxiv 038448; doi: https://doi.org/10.1101/038448
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Gene Expression Signatures of Sporadic ALS Motor Neuron Populations
Ranjan Batra, Kasey Hutt, Anthony Vu, Stuart J. Rabin, Michael W. Baughn, Ryan T. Libby, Shawn Hoon, John Ravits, Gene W. Yeo
bioRxiv 038448; doi: https://doi.org/10.1101/038448

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