Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 22, Pages 5574-5586Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3582-16.2017
Keywords
ALS; microRNAs; miRAP; motor neuron; motor neuron disease; TRAP
Categories
Funding
- Project5 for ALS
- National Institute of Neurological Disorders and Stroke-National Institutes of Health [K08NS074194, R01NS078398, F31NS077781, F31NS092340]
- Robert Packard Center for ALS Research
- University of Missouri Spinal Cord Injury and Disease Research Program
- Hope Center for Neurological Disorders
- Brain and Behavior Research Foundation
- Departments of Neurology and Psychiatry at Washington University School of Medicine
- Washington University School of Medicine, Children's Discovery Institute of Washington University
- St. Louis Children's Hospital
- Foundation for Barnes-Jewish Hospital
- National Institute for Neurological Disorders and Stroke-National Institutes of Health [NS086741]
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.
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