MicroRNA profiling reveals marker of motor neuron disease in ALS models

Mariah L. Hoye, Erica D. Koval, Amy J. Wegener, Theodore S. Hyman, Chengran Yang, David R. O’Brien, Rebecca L. Miller, Tracy Cole, Kathleen M. Schoch, Tao Shen, Tomonori Kunikata, Jean Philippe Richard, David H. Gutmann, Nicholas J. Maragakis, Holly B. Kordasiewicz, Joseph D. Dougherty, Timothy M. Miller

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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. Micron RNAs (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.

Original languageEnglish
Pages (from-to)5574-5586
Number of pages13
JournalJournal of Neuroscience
Volume37
Issue number22
DOIs
StatePublished - May 31 2017

Keywords

  • ALS
  • MiRAP
  • MicroRNAs
  • Motor neuron
  • Motor neuron disease
  • TRAP

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