Date of Award
Spring 5-15-2018
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MNs) in the brain and spinal cord. However, the pathophysiology underlying MN selective vulnerability is unclear, especially considering ALS-causative mutations are in ubiquitously expressed proteins. Moreover, despite the preferential degeneration of MNs in ALS, the surrounding cell types are not bystanders, but greatly contribute to disease progression. Thus, to better understand MN vulnerability in ALS, we characterized the distinct microRNA (miRNAs) expression profile of MNs as compared to other central nervous system cell types. We focused on miRNAs because they have broad regulatory capacity and often exhibit cell type-enriched expression, and thus, may be important determinants of MN identity. Additionally, we predicted that MN-enriched miRNA profiles would inform on novel markers of MN disease and mechanisms of ALS pathogenesis. To this end, we identified MN-enriched miRNA expression and found they may functionally define postnatal MN identity. Consistent with a critical role in MNs, we found that single nucleotide polymorphisms (SNPs) in MN-enriched miR-218 were significantly more prevalent in singleton ALS patients than controls, suggesting SNPs in MN-enriched miRNAs may confer a genetic pre-disposition to MN disease. Importantly, we also demonstrated that the levels of MN-enriched miR-218 are elevated in ALS rodent model cerebrospinal fluid (CSF) and are highly correlated with MN loss. Treatment of ALS model rats with a MN-sparing therapy prevented the increase in miR-218 CSF levels, demonstrating that miR-218 is a MN-specific and pharmacodynamic biomarker of MN disease. We further validated that miR-218 was also applicable to human MN disease, as the miR-218 CSF levels of Spinal Muscular Atrophy patients also responded to a MN-sparing therapy. Finally, we unexpectedly observed that extracellular, MN-derived miR-218 also contributes to ALS disease progression, as it can be taken up by astrocytes and functionally contribute to their dysfunction in ALS model mice. These data define a novel mechanism in neurodegeneration whereby diseased neurons can communicate, through extracellular miRNAs, with surrounding glia and deleteriously modify their phenotype. Overall, this work demonstrates that applying a cell-type specific focus to diseases that exhibit selective vulnerability can successfully uncover novel biomarkers, genetic risk factors, and mechanisms of disease.
Language
English (en)
Chair and Committee
Timothy M. Miller
Committee Members
Joseph D. Dougherty, Kathleen B. Hall, Conrad C. Weihl, Sergej Djuranovic,
Recommended Citation
Hoye, Mariah Lawler, "Defining Motor Neuron-Enriched microRNAs Reveals Novel Biomarkers and Genetic Causes of Motor Neuron Disease and Uncovers New Mechanisms of Glial Dysfunction in ALS" (2018). Arts & Sciences Electronic Theses and Dissertations. 1537.
https://openscholarship.wustl.edu/art_sci_etds/1537
Comments
Permanent URL: https://doi.org/10.7936/K71C1W9H